Piperazine derivatives having multimodal activity against pain

ABSTRACT

The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opiod receptor and more particularly to piperazine compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

FIELD OF THE INVENTION

The present invention relates to compounds having dual pharmacologicalactivity towards both the sigma (σ) receptor, and the μ-opiod receptor(MOR or mu-opioid) and more particularly to piperidine compounds havingthis pharmacological activity, to processes of preparation of suchcompounds, to pharmaceutical compositions comprising them, and to theiruse in therapy, in particular for the treatment of pain.

BACKGROUND OF THE INVENTION

The adequate management of pain constitutes an important challenge,since currently available treatments provide in many cases only modestimprovements, leaving many patients unrelieved [Turk D C, Wilson H D,Cahana A. Treatment of chronic non-cancer pain. Lancet 377, 2226-2235(2011)]. Pain affects a big portion of the population with an estimatedprevalence of around 20% and its incidence, particularly in the case ofchronic pain, is increasing due to the population ageing. Additionally,pain is clearly related to comorbidities, such as depression, anxietyand insomnia, which lead to important productivity losses andsocio-economical burden [Goldberg D S, McGee S J. Pain as a globalpublic health priority. BMC Public Health. 11, 770 (2011)]. Existingpain therapies include non-steroidal anti-inflammatory drugs (NSAIDs),opioid agonists, calcium channel blockers and antidepressants, but theyare much less than optimal regarding their safety ratio. All of themshow limited efficacy and a range of secondary effects that precludetheir use, especially in chronic settings.

As mentioned before, there are few available therapeutic classes for thetreatment of pain, and opioids are among the most effective, especiallywhen addressing severe pain states. They act through three differenttypes of opioid receptors (mu, kappa and gamma) which are transmembraneG-protein coupled receptors (GPCRs). Still, the main analgesic action isattributed to the activation of the p-opioid receptor (MOR). However,the general administration of MOR agonists is limited due to theirimportant side effects, such as constipation, respiratory depression,tolerance, emesis and physical dependence [Meldrum, M. L. (Ed.). Opioidsand Pain Relief: A Historical Perspective. Progress in Pain Research andManagement, Vol 25. IASP Press, Seattle, 2003]. Additionally, MORagonists are not optimal for the treatment of chronic pain as indicatedby the diminished effectiveness of morphine against chronic painconditions. This is especially proven for the chronic pain conditions ofneuropathic or inflammatory origin, in comparison to its high potencyagainst acute pain. The finding that chronic pain can lead to MORdown-regulation may offer a molecular basis for the relative lack ofefficacy of morphine in long-term treatment settings [Dickenson, A. H.,Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur JPain 9, 113-6 (2005)]. Moreover, prolonged treatment with morphine mayresult in tolerance to its analgesic effects, most likely due totreatment-induced MOR down-regulation, internalization and otherregulatory mechanisms. As a consequence, long-term treatment can resultin substantial increases in dosing in order to maintain a clinicallysatisfactory pain relief, but the narrow therapeutic window of MORagonists finally results in unacceptable side effects and poor patientcompliance.

The sigma-1 (σ₁) receptor was discovered 35 years ago and initiallyassigned to a new subtype of the opioid family, but later on and basedon the studies of the enantiomers of SKF-10,047, its independent naturewas established. The first link of the σ₁ receptor to analgesia wasestablished by Chien and Pasternak [Chien C C, Pasternak G W. Sigmaantagonists potentiate opioid analgesia in rats. Neurosci. Lett. 190,137-9 (1995)], who described it as an endogenous anti-opioid system,based on the finding that σ₁ receptor agonists counteracted opioidreceptor mediated analgesia, while σ₁ receptor antagonists, such ashaloperidol, potentiated it.

Many additional preclinical evidences have indicated a clear role of theσ₁ receptor in the treatment of pain [Zamanillo D, Romero L, Merlos M,Vela J M. Sigma 1 receptor: A new therapeutic target for pain. Eur. J.Pharmacol, 716, 78-93 (2013)]. The development of the σ₁ receptorknockout mice, which show no obvious phenotype and perceive normallysensory stimuli, was a key milestone in this endeavour. In physiologicalconditions the responses of the σ₁ receptor knockout mice to mechanicaland thermal stimuli were found to be undistinguishable from WT ones butthey were shown to possess a much higher resistance to develop painbehaviours than WT mice when hypersensitivity entered into play. Hence,in the σ₁ receptor knockout mice capsaicin did not induce mechanicalhypersensitivity, both phases of formalin-induced pain were reduced, andcold and mechanical hypersensitivity were strongly attenuated afterpartial sciatic nerve ligation or after treatment with paclitaxel, whichare models of neuropathic pain. Many of these actions were confirmed bythe use of σ₁ receptor antagonists and led to the advancement of onecompound, S1RA, into clinical trials for the treatment of different painstates. Compound S1RA exerted a substantial reduction of neuropathicpain and anhedonic state following nerve injury (i.e., neuropathic painconditions) and, as demonstrated in an operant self-administrationmodel, the nerve-injured mice, but not sham-operated mice, acquired theoperant responding to obtain it (presumably to get pain relief),indicating that σ₁ receptor antagonism relieves neuropathic pain andalso address some of the comorbidities (i.e., anhedonia, a core symptomin depression) related to pain states.

Pain is multimodal in nature, since in nearly all pain states severalmediators, signaling pathways and molecular mechanisms are implicated.Consequently, monomodal therapies fail to provide complete pain relief.Currently, combining existing therapies is a common clinical practiceand many efforts are directed to assess the best combination ofavailable drugs in clinical studies [Mao J, Gold M S, Backonja M.Combination drug therapy for chronic pain: a call for more clinicalstudies. J. Pain 12, 157-166 (2011)]. Hence, there is an urgent need forinnovative therapeutics to address this unmet medical need.

As mentioned previously, opioids are among the most potent analgesicsbut they are also responsible for various adverse effects whichseriously limit their use.

Accordingly, there is still a need to find compounds that have analternative or improved pharmacological activity in the treatment ofpain, being both effective and showing the desired selectivity, andhaving good “drugability” properties, i.e. good pharmaceuticalproperties related to administration, distribution, metabolism andexcretion.

Thus, the technical problem can therefore be formulated as findingcompounds that have an alternative or improved pharmacological activityin the treatment of pain.

In view of the existing results of the currently available therapies andclinical practices, the present invention offers a solution by combiningin a single compound binding as a ligand to two different receptorsrelevant for the treatment of pain. This was mainly achieved byproviding the compound according to the invention that bind both to theμ-opiod receptor and to the σ₁ receptor.

SUMMARY OF THE INVENTION

In this invention a family of structurally distinct piperazinederivatives which have a dual pharmacological activity towards both thesigma (σ) receptor, and the μ-opiod receptor was identified thus solvingthe above problem of identifying alternative or improved pain treatmentsby offering such dual compounds.

The invention is in one aspect directed to a compound having a dualactivity binding to the σ₁ receptor and the μ-opioid receptor for use inthe treatment of pain.

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opioid receptor it is a very preferred embodiment if thecompound has a binding expressed as K_(i) which is <100 nm for bothreceptors, the μ-opioid receptor and the σ₁ receptor.

The invention is directed in a main aspect to a compound of generalformula (I),

wherein R¹, R², R⁵, V¹, V², V³, W, X, Y, Z and m are as defined below inthe detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a family of structurally distinctpiperazine derivatives which have a dual pharmacological activitytowards both the sigma (σ) receptor, and the μ-opiod receptor wasidentified thus solving the above problem of identifying alternative orimproved pain treatments by offering such dual compounds.

The invention is in one aspect directed to a compound having a dualactivity binding to the σ₁ receptor and the μ-opioid receptor for use inthe treatment of pain.

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opioid receptor it is a very preferred embodiment if thecompound has a binding expressed as K_(i) which is <100 nm for bothreceptors, the μ-opioid receptor and the σ₁ receptor.

The applicant has surprisingly found that the problem on which thepresent invention is based can be solved by using a multimodal balancedanalgesic approach combining two different synergistic activities in asingle drug (i.e., dual ligands which are bifunctional and bind to MORand to σ₁ receptor), thereby enhancing the opioid analgesia through theσ₁ activation without increasing the undesirable side effects. Thissupports the therapeutic value of a dual MOR/σ₁ receptor compoundwhereby the σ₁ receptor binding component acts as an intrinsic adjuvantof the MOR binding component.

This solution offered the advantage that the two mechanisms complementeach other in order to treat pain and chronic pain using lower andbetter tolerated doses needed based on the potentiation of analgesia butavoiding the adverse events of p opioid receptor agonists.

A dual compound that possess binding to both the μ-opiod receptor and tothe σ₁ receptor shows a highly valuable therapeutic potential byachieving an outstanding analgesia (enhanced in respect to the potencyof the opioid component alone) with a reduced side-effect profile(safety margin increased compared to that of the opioid component alone)versus existing opiod therapies.

Advantageously, the dual compounds according to the present inventionwould in addition show one or more the following functionalities: σ₁receptor antagonism and MOR agonism. It has to be noted, though, thatboth functionalities “antagonism” and “agonism” are also sub-divided intheir effect into subfunctionalities like partial agonism or inverseagonism. Accordingly, the functionalities of the dual compound should beconsidered within a relatively broad bandwidth.

An antagonist on one of the named receptors blocks or dampensagonist-mediated responses. Known subfunctionalities are neutralantagonists or inverse agonists.

An agonist on one of the named receptors increases the activity of thereceptor above its basal level. Known subfunctionalities are fullagonists, or partial agonists.

In addition, the two mechanisms complement each other since MOR agonistsare only marginally effective in the treatment of neuropathic pain,while σ₁ receptor antagonists show outstanding effects in preclinicalneuropathic pain models. Thus, the σ₁ receptor component adds uniqueanalgesic actions in opioid-resistant pain. Finally, the dual approachhas clear advantages over MOR agonists in the treatment of chronic painas lower and better tolerated doses would be needed based on thepotentiation of analgesia but not of the adverse events of MOR agonists.

A further advantage of using designed multiple ligands is a lower riskof drug-drug interactions compared to cocktails or multi-componentdrugs, thus involving simpler pharmacokinetics and less variabilityamong patients. Additionally, this approach may improve patientcompliance and broaden the therapeutic application in relation tomonomechanistic drugs, by addressing more complex aetiologies. It isalso seen as a way of improving the R&D output obtained using the “onedrug-one target” approach, which has been questioned over the last years[Bornot A, Bauer U, Brown A, Firth M, Hellawell C, Engkvist O.Systematic Exploration of Dual-Acting Modulators from a CombinedMedicinal Chemistry and Biology Perspective. J. Med. Chem, 56, 1197-1210(2013)].

In a particular aspect, the present invention is directed to compoundsof general formula (I):

-   -   wherein    -   m is 1 or 2;    -   one of V¹, V² and V³ is selected from nitrogen or carbon while        the other two are carbon;    -   R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸,        —SR⁶, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl; R² is hydrogen, halogen (F, Cl, I, Br), —NR⁶R⁷,        —SR⁶, —OR⁶, substituted or unsubstituted alkyl, substituted of        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl;    -   or    -   R¹ and R² are bonded to neighbouring atoms in the ring and        together with these atoms form a saturated or unsaturated,        substituted or unsubstituted ring, fused to    -   the ring

of the corestructure of formula I, which may be condensed with a furtherunsubstituted or substituted ring system;

-   -   R⁵ is hydrogen, hydroxy or CH₃;    -   R⁶, R⁷ and R⁸ are independent from each other and selected from        the group formed by hydrogen, substituted or unsubstituted        alkyl, substituted of unsubstituted cycloalkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl and substituted or        unsubstituted heterocyclyl, or R⁶, R⁷ or R⁸ together with their        respective connecting carbon or nitrogen atom may form a        cycloalkylic or heterocyclic 4 to 7-membered ring;    -   and wherein W, X, Y and Z are selected from carbon, nitrogen, or        oxygen while W—X—Y—Z are forming together with the bridging        C-atom, that is connected to the core scaffold, a 5-membered        heterocyclic ring, which is substituted on one of W,    -   X, Y or Z by

-   -   -   wherein        -   n is 0 or 1;        -   R³ is substituted or unsubstituted alkyl, CONR⁶R⁷,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted aryl and substituted or            unsubstituted heterocyclyl;        -   R⁴ is hydrogen, substituted or unsubstituted alkyl,            substituted of unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted of unsubstituted aryl and substituted of            unsubstituted heterocyclyl;

    -   and wherein

is selected from

-   -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof.    -   In another embodiment the compound according to the        invention—especially according to general formula (I)—is        optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt therefore a corresponding solvate thereof.    -   In another embodiment the compound according to the        invention—especially according to general formula (I)—is        optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof.    -   In another embodiment the compound according to the        invention—especially according to general formula (I)—is        optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio.    -   In one embodiment one or more of the following provisos are        applying:        -   with the proviso that if V¹, V² and V³ are carbon and one of            W, X, Y or Z is

-   -   -   -   then R² may not be —OCH₃ in meta position;

    -   and/or        -   with the proviso that if V¹, V² and V³ are carbon, n is 0            and R³ is —CH₃ or —C₂H₅, then neither R¹ nor R² may be —NH₂            in meta position;

    -   and/or

    -   with the proviso that if n is 0, R³ may not be alkyl;

    -   and/or

    -   with the proviso that the compound may not be Benzenamine,        3-[4-[2-(3-methyl-5-isoxazolyl)ethyl]-1-piperazinyl];

    -   and/or

    -   with the proviso that the compound may not be Benzenamine,        3-[4-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-piperazinyl];

    -   and/or

    -   with the proviso that the compound may not be Benzenamine,        3-[4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-piperazinyl].

In one embodiment the following substituents are preferred:

-   -   wherein said aryl or heterocyclyl in R¹, and/or said cycloalkyl,        aryl or heterocyclyl in R², or said ring formed by R¹ and R² or        the ring condensed to it, if substituted, is substituted with        one or more substituents selected from halogen, —R⁹, —OR⁹, —NO₂,        —NR⁹R^(9′), NR⁹C(O)R^(9′), —NR⁹S(O)₂R^(9′), —S(O)₂NR⁹R^(9′),        —NR⁹C(O)NR^(9′)R^(9″), —SR⁹, —S(O)R⁹, S(O)₂R⁹, —CN, haloalkyl,        haloalkoxy, —C(O)OR⁹, —C(O)NR⁹R^(9′), —OCH₂CH₂OH,        —NR⁹S(O)₂NR^(9′)R^(9′). and C(CH₃)₂OR⁹;    -   wherein said alkyl, alkenyl or alkynyl in R², if substituted, is        substituted with one or more substituents selected from —OR⁹,        halogen, —CN, haloalkyl, haloalkoxy, —NR⁹R^(9′″), —SR⁹, —S(O)R⁹,        and —S(O)₂R⁹;        -   wherein R⁹, R^(9′) and R^(9″) are independently selected            from hydrogen, unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆            alkenyl, unsubstituted C₂₋₆ alkynyl;        -   and wherein R^(9′″) is selected from hydrogen, unsubstituted            C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl, unsubstituted C₂₋₆            alkynyl and -Boc;    -   wherein said cycloalkyl, aryl or heterocyclyl in R⁶, in R⁷,        and/or in R⁸, if substituted, is substituted with one or more        substituents selected from halogen, —R¹⁰, —OR¹⁰, —NO₂,        —NR¹⁰R^(10′″), NR¹⁰C(O)R^(10′), —NR¹⁰S(O)₂R^(10′),        —S(O)₂NR¹⁰R^(10′), —NR¹⁰C(O)NR^(10′)R^(10″), —SR¹⁰, —S(O)R¹⁰,        S(O)₂R¹⁰, —CN, haloalkyl, haloalkoxy, —C(O)OR¹⁰,        —C(O)NR¹⁰R^(10′), —OCH₂CH₂OH, NR¹⁰S(O)₂NR^(10′)R^(10″) and        C(CH₃)₂OR¹⁰;    -   wherein said alkyl, alkenyl, or alkynyl in R⁶, in R⁷, ad/or in        R⁸, if substituted, is substituted with one or more substituents        selected from —OR¹⁰, halogen, —CN, haloalkyl, haloalkoxy,        —NR¹⁰R^(10″), —SR¹⁰, —S(O)R¹⁰, and —S(O)₂R¹⁰;        -   wherein R¹⁰, R^(10′) and R^(10″) are independently selected            from hydrogen, unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆            alkenyl, unsubstituted C₂₋₆ alkynyl;        -   and wherein R^(10″) is selected from hydrogen, unsubstituted            C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl, unsubstituted C₂₋₆            alkynyl and -Boc;    -   wherein said cycloalkyl, aryl or heterocyclyl in R³ and/or in        R⁴, if substituted, is substituted with one or more substituents        selected from halogen, —R¹¹, —OR¹¹, —NO₂, —NR¹¹R^(11″),        NR¹¹C(O)R^(11′), —NR¹¹S(O)₂R^(11′), —S(O)₂NR¹¹R^(11′),        NR¹¹C(O)NR^(11′)R^(11″), —SR¹¹, —S(O)R¹¹, S(O)₂R¹¹, —CN,        haloalkyl, haloalkoxy, —C(O)OR¹¹, —C(O)NR¹¹R^(11′), —OCH₂CH₂OH,        —NR¹¹S(O)₂NR^(11′)R^(11″) and C(CH₃)₂OR¹¹;    -   wherein said alkyl, alkenyl, or alkynyl in R³ and/or in R⁴, if        substituted, is substituted with one or more substituents        selected from —OR¹¹, halogen, —CN, haloalkyl, haloalkoxy,        —NR¹¹R^(11″), —SR¹¹, —S(O)R¹¹, and —S(O)₂R¹¹;        -   wherein R¹¹, R^(11′) and R^(11″) are independently selected            from hydrogen, unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆            alkenyl, unsubstituted C₂₋₆ alkynyl;        -   and wherein R^(11″) is selected from hydrogen, unsubstituted            C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl, unsubstituted C₂₋₆            alkynyl and -Boc.

In one other embodiment the following substituents are preferred:

-   -   wherein said aryl or heterocyclyl in R¹, and/or said cycloalkyl,        aryl or heterocyclyl in R², or said ring formed by R¹ and R² or        the ring condensed to it, if substituted, is substituted with        one or more substituents selected from OH, SH, ═O, halogen (F,        Cl, Br, I), CN, NO₂, COOH, R_(z), O—R_(z), S—R_(z), —C(O)—R_(z),        —C(O)—O—R_(z), NR_(x)R_(y); a substituted or unsubstituted aryl        or alkyl-aryl; a substituted or unsubstituted cycloalkyl or        alkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl or        alkyl-heterocyclyl;    -   wherein said alkyl, alkenyl or alkynyl in R², if substituted, is        substituted with one or more substituents selected from F, Cl,        Br, I, NH₂, SH or OH, —C(O)OH, or —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br);        -   wherein R_(z) is selected from saturated or unsaturated,            linear or branched, substituted or unsubstituted C₁₋₆ alkyl,            unsubstituted C₂₋₆ alkenyl, unsubstituted C₂₋₆ alkynyl;        -   with R_(x) and R_(y) independently being either H or a            saturated or unsaturated, linear or branched, substituted or            unsubstituted C₁₋₆-alkyl;    -   wherein said cycloalkyl, aryl or heterocyclyl in R⁶, in R⁷,        and/or in R⁸, if substituted, is substituted with one or more        substituents selected from OH, SH, ═O, halogen (F, Cl, Br, I),        CN, NO₂, COOH, R_(z), O—R_(z), S—R_(z), —C(O)—R_(z),        —C(O)—O—R_(z), NR_(x)R_(y); a substituted or unsubstituted aryl        or alkyl-aryl; a substituted or unsubstituted cycloalkyl or        alkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl or        alkyl-heterocyclyl;    -   wherein said alkyl, alkenyl or alkynyl in R⁶, in R⁷, and/or in        R⁸, if substituted, is substituted with one or more substituents        selected from F, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or        —OC₁₋₄alkyl being unsubstituted or substituted by one or more of        OH or halogen (F, Cl, I, Br);        -   wherein R_(z) is selected from saturated or unsaturated,            linear or branched, substituted or unsubstituted C₁₋₆ alkyl,            unsubstituted C₂₋₆ alkenyl, unsubstituted C₂₋₆ alkynyl;        -   with R_(x) and R_(y) independently being either H or a            saturated or unsaturated, linear or branched, substituted or            unsubstituted C₁₋₆-alkyl;    -   wherein said cycloalkyl, aryl or heterocyclyl in R³ and/or in        R⁴, if substituted, is substituted with one or more substituents        selected from OH, SH, ═O, halogen (F, Cl, Br, I), CN, NO₂, COOH,        R_(z), O—R_(z), S—R_(z), —C(O)—R_(z), —C(O)—O—R_(z),        NR_(x)R_(y); a substituted or unsubstituted aryl or alkyl-aryl;        a substituted or unsubstituted cycloalkyl or alkyl-cycloalkyl; a        substituted or unsubstituted heterocyclyl or alkyl-heterocyclyl;    -   wherein said alkyl, alkenyl or alkynyl in R³ and/or in R⁴, if        substituted, is substituted with one or more substituents        selected from F, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or        —OC₁₋₄alkyl being unsubstituted or substituted by one or more of        OH or halogen (F, Cl, I, Br);        -   wherein R_(z) is selected from saturated or unsaturated,            linear or branched, substituted or unsubstituted C₁₋₆ alkyl,            unsubstituted C₂₋₆ alkenyl, unsubstituted C₂₋₆ alkynyl;        -   with R_(x) and R_(y) independently being either H or a            saturated or unsaturated, linear or branched, substituted or            unsubstituted C₁₋₆-alkyl.

In one further embodiment the following substituents are preferred

-   -   wherein said aryl in R¹ and/or in R², or said ring formed by R¹        and R² or the ring condensed to it, if a substituted aryl, is        substituted with one or more substituents selected from halogen        (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH, —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted or        substituted by one or more of OH or halogen (F, Cl, I, Br);    -   wherein said heterocyclyl in R¹ and/or said heterocyclyl or        cycloalkyl in R², or said ring formed by R¹ and R² or the ring        condensed to it, if a substituted heterocyclyl or cycloalkyl, is        substituted with one or more substituents selected from halogen        (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —C(O)OH, —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted or        substituted by one or more of OH or halogen (F, Cl, I, Br);    -   wherein said alkyl, alkenyl or alkynyl in R², if substituted, is        substituted with one or more substituents selected from F, Cl,        Br, I, NH₂, SH or OH, —C(O)OH, or —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br);    -   wherein said aryl in R⁶, in R⁷, and/or in R⁸, if a substituted        aryl, is substituted with one or more substituents selected from        halogen (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH, —OC₁₋₄alkyl        being unsubstituted or substituted by one or more of OH or        halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted        or substituted by one or more of OH or halogen (F, Cl, I, Br);    -   wherein said heterocyclyl or cycloalkyl in in R⁶, in R⁷, and/or        in R⁸, if a substituted heterocyclyl or cycloalkyl, is        substituted with one or more substituents selected from halogen        (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —C(O)OH, —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted or        substituted by one or more of OH or halogen (F, Cl, I, Br);    -   wherein said alkyl, alkenyl or alkynyl in R⁶, in R⁷, and/or in        R⁸, if substituted, is substituted with one or more substituents        selected from F, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or        —OC₁₋₄alkyl being unsubstituted or substituted by one or more of        OH or halogen (F, Cl, I, Br);    -   wherein said aryl in R³ and/or in R⁴, if a substituted aryl, is        substituted with one or more substituents selected from halogen        (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH, —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted or        substituted by one or more of OH or halogen (F, Cl, I, Br);    -   wherein said heterocyclyl or cycloalkyl in in R³ and/or in R⁴,        if a substituted heterocyclyl or cycloalkyl, is substituted with        one or more substituents selected from halogen (F, Cl, I, Br),        —OH, —NH₂, —SH, ═O, —C(O)OH, —OC₁₋₄alkyl being unsubstituted or        substituted by one or more of OH or halogen (F, Cl, I, Br), —CN,        or —C₁₋₄alkyl being unsubstituted or substituted by one or more        of OH or halogen (F, Cl, I, Br);    -   wherein said alkyl, alkenyl or alkynyl in R³ and/or in R⁴, if        substituted, is substituted with one or more substituents        selected from F, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or        —OC₁₋₄alkyl being unsubstituted or substituted by one or more of        OH or halogen (F, Cl, I, Br).

When different radicals R¹ to R¹¹, R_(x), R_(y) or R_(z) are presentsimultaneously in the different Formulas of the present invention theymay be identical or different.

In the general context of this invention, alkyl is understood as meaningsaturated, linear or branched hydrocarbons, which may be unsubstitutedor substituted once or several times. It encompasses e.g. —CH₃ and—CH₂—CH₃. In these radicals, C₁₋₂-alkyl represents C1- or C2-alkyl,C₁₋₃-alkyl represents C1-, C2- or C3-alkyl, C₁₋₄-alkyl represents C1-,C2-, C3- or C4-alkyl, C₁₋₅-alkyl represents C1-, C2-, C3-, C4-, orC5-alkyl, C1-6-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl,C₁₋₇-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl,C₁₋₈-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl,C₁₋₁₀-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- orC10-alkyl and C₁₋₁₈-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl.The alkyl radicals are preferably methyl, ethyl, propyl, methylethyl,butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl,1-methylpentyl, if substituted also CHF₂, CF₃ or CH₂OH etc. Preferablyalkyl is understood in the context of this invention as C₁₋₈alkyl likemethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl;preferably is C₁₋₆alkyl like methyl, ethyl, propyl, butyl, pentyl, orhexyl; more preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl.

Alkenyl is understood as meaning unsaturated, linear or branchedhydrocarbons, which may be unsubstituted or substituted once or severaltimes. It encompasses groups like e.g. —CH≡CH—CH₃. The alkenyl radicalsare preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in thecontext of this invention alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl likeethylene, propylene, butylene, pentylene, hexylene, heptylene oroctylene; or is C₁₋₆-alkenyl like ethylene, propylene, butylene,pentylene, or hexylene; or is C₁₋₄-alkenyl, like ethylene, propylene, orbutylenes.

Alkynyl is understood as meaning unsaturated, linear or branchedhydrocarbons, which may be unsubstituted or substituted once or severaltimes. It encompasses groups like e.g. —C≡C—CH₃ (1-propinyl). Preferablyalkynyl in the context of this invention is C₂₋₁₀-alkynyl orC₂₋₈-alkynyl like ethyne, propyne, butyene, pentyne, hexyne, heptyne, oroctyne; or is C₂₋₆-alkynyl like ethyne, propyne, butyene, pentyne, orhexyne; or is C₂₋₄-alkynyl like ethyne, propyne, butyene, pentyne, orhexyne.

In the context of this invention cycloalkyl is understood as meaningsaturated and unsaturated (but not aromatic) cyclic hydrocarbons(without a heteroatom in the ring), which can be unsubstituted or onceor several times substituted. Furthermore, C₃₋₄-cycloalkyl representsC3- or C4-cycloalkyl, C₃₋₅-cycloalkyl represents C3-, C4- orC5-cycloalkyl, C₃₋₆-cycloalkyl represents C3-, C4-, C5- orC6-cycloalkyl, C₃₋₇-cycloalkyl represents C3-, C4-, C5-, C6- orC7-cycloalkyl, C₃₋₈-cycloalkyl represents C3-, C4-, C5-, C6-, C7- orC8-cycloalkyl, C₄₋₅-cycloalkyl represents C4- or C5-cycloalkyl,C₄₋₆-cycloalkyl represents C4-, C5- or C6-cycloalkyl, C₄₋₇-cycloalkylrepresents C4-, C5-, C6- or C7-cycloalkyl, C₅₋₆-cycloalkyl representsC5- or C6-cycloalkyl and C₅₋₇-cycloalkyl represents C5-, C6- orC7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl,cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl,cyclohexyl, cycloheptyl, cyclooctyl, and also adamantly. Preferably inthe context of this invention cycloalkyl is C₃₋₈cycloalkyl likecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl; or is C₃₋₇cycloalkyl like cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl; or is C₃₋₆cycloalkyl likecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especiallycyclopentyl or cyclohexyl.

In the general connection with alkyl, alkenyl, alkynyl andO-alkyl—unless defined otherwise—the term substituted in the context ofthis invention is understood as meaning replacement of at least onehydrogen radical on a carbon atom by F, Cl, Br, I, NH₂, SH or OH,—C(O)OH, or —OC₁₋₄alkyl being unsubstituted or substituted by one ormore of OH or halogen (F, Cl, I, Br). More than one replacement on thesame molecule and also on the same carbon atom is possible with the sameor different substituents. This includes for example 3 hydrogens beingreplaced on the same C atom, as in the case of CF₃, or at differentplaces of the same molecule, as in the case of e.g. —CH(OH)—CH═CH—CHCl₂.

More than one replacement on the same molecule and also on the samecarbon atom is possible with the same or different substituents. Thisincludes for example 3 hydrogens being replaced on the same C atom, asin the case of CF₃, or at different places of the same molecule, as inthe case of e.g. —CH(OH)—CH═CH—CHCl₂.

In the general context of this invention haloalkyl is understood asmeaning an alkyl being substituted once or several times by a halogen(selected from F, Cl, Br, I). It encompasses e.g. —CH₂Cl, —CH₂F, —CHCl₂,—CHF₂, —CCl₃, —CF₃ and —CH₂—CHCl₂. Preferably haloalkyl is understood inthe context of this invention as halogen-substituted C₁₋₄-alkylrepresenting halogen substituted C1-, C2-, C3- or C4-alkyl. Thehalogen-substituted alkyl radicals are thus preferably methyl, ethyl,propyl, and butyl. Preferred examples include —CH₂Cl, —CH₂F, —CHCl₂,—CHF₂, and —CF₃.

In the context of this invention haloalkoxy is understood as meaning an—O-alkyl being substituted once or several times by a halogen (selectedfrom F, Cl, Br, I). It encompasses e.g. —OCH₂Cl, —OCH₂F, —OCHCl₂,—OCHF₂, —OCCl₃, —OCF₃ and —OCH₂—CHC₂. Preferably haloalkoxy isunderstood in the context of this invention as halogen-substituted—OC₁₋₄-alkyl representing halogen substituted C1-, C2-, C3- orC4-alkoxy. The halogen-substituted alkyl radicals are thus preferablyO-methyl, O-ethyl, O-propyl, and O-butyl. Preferred examples include—OCH₂Cl, —OCH₂F, —OCHCl₂, —OCHF₂, and —OCF₃.

Most preferably in connection with alkyl, alkenyl, alkynyl or O-alkyl,substituted is understood in the context of this invention that anyalkyl, alkenyl, alkynyl or O-alkyl which is substituted is substitutedby one or more of halogen (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH, or—OC₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br).

Aryl is understood as meaning ring systems with at least one aromaticring but without heteroatoms even in only one of the rings. Examples arephenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, inparticular 9H-fluorenyl or anthracenyl radicals, which can beunsubstituted or once or several times substituted. Most preferably arylis understood in the context of this invention as phenyl, naphtyl oranthracenyl, preferably is phenyl.

In the context of this invention alkylaryl is understood as meaning anaryl group (see above) being connected to another atom through aC₁₋₆-alkyl (see above), which may be branched or linear and isunsubstituted or substituted once or several times. Thus, in the contextof this invention alkylaryl is understood as meaning an aryl group (seeabove) being connected to another atom through a C₁₋₆-alkyl (see above).The alkyl may be branched or linear and is unsubstituted, while the arylmay be unsubstituted or substituted once or several times. Preferablyalkylaryl is understood as meaning an aryl group (see above) beingconnected to another atom through 1 to 4 (—CH₂—) groups. Most preferablyalkylaryl is benzyl (i.e. —CH₂-phenyl).

In the context of this invention alkylheterocyclyl is understood asmeaning a heterocyclyl group being connected to another atom through aC₁₋₆-alkyl (see above), which may be branched or linear and isunsubstituted or substituted once or several times. Thus, in the contextof this invention alkylheterocyclyl is understood as meaning aheterocyclyl group (see above) being connected to another atom through aC₁₋₆-alkyl (see above). The alkyl may be branched or linear and isunsubstituted, while the heterocyclyl may be unsubstituted orsubstituted once or several times. Preferably alkylheterocyclyl isunderstood as meaning an heterocyclyl group (see above) being connectedto another atom through 1 to 4 (—CH₂—) groups. Most preferablyalkylheterocyclyl is —CH₂-pyridine.

In the context of this invention alkylcycloalkyl is understood asmeaning a cycloalkyl group being connected to another atom through aC₁₋₆-alkyl (see above), which may be branched or linear and isunsubstituted or substituted once or several times. Thus, in the contextof this invention alkylcycloalkyl is understood as meaning a cycloalkylgroup (see above) being connected to another atom through a C₁₋₆-alkyl(see above). The alkyl may be branched or linear and is unsubstituted,while the cycloalkyl may be substituted once or several times.Preferably alkylcycloalkyl is understood as meaning a cycloalkyl group(see above) being connected to another atom through 1 to 4 (—CH₂—)groups. Most preferably alkylcycloalkyl is —CH₂-cyclopropyl.

A heterocyclyl radical or group (also called heterocyclyl hereinafter)is understood as meaning heterocyclic ring systems, with at least onesaturated or unsaturated ring which contains one or more heteroatomsfrom the group consisting of nitrogen, oxygen and/or sulfur in the ring.A heterocyclic group can also be substituted once or several times.Examples include non-aromatic heterocyclyls such as tetrahydropyrane,oxazepane, morpholine, piperidine, pyrrolidine as well as heteroarylssuch as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine,benzo-1,2,5-thiadiazole, benzothiazole, indole, benzotriazole,benzodioxolane, benzodioxane, carbazole and quinazoline.

Subgroups inside the heterocyclyls as understood herein includeheteroaryls and non-aromatic heterocyclyls.

-   -   the heteroaryl (being equivalent to heteroaromatic radicals or        aromatic heterocyclyls) is an aromatic heterocyclic ring system        of one or more rings of which at least one aromatic ring        contains one or more heteroatoms from the group consisting of        nitrogen, oxygen and/or sulfur in the ring; preferably is an        aromatic heterocyclic ring system of one or two rings of which        at least one aromatic ring contains one or more heteroatoms from        the group consisting of nitrogen, oxygen and/or sulfur in the        ring, more preferably is selected from furan, benzofuran,        thiophene, benzothiophene, pyrrole, pyridine, pyrimidine,        pyrazine, quinoline, isoquinoline, phthalazine, benzothiazole,        indole, benzotriazole, carbazole, quinazoline, thiazole,        imidazole, pyrazole, oxazole, thiophene and benzimidazole;    -   the non-aromatic heterocyclyl is a heterocyclic ring system of        one or more rings of which at least one ring—with this (or        these) ring(s) then not being aromatic—contains one or more        heteroatoms from the group consisting of nitrogen, oxygen and/or        sulfur in the ring; preferably is a heterocyclic ring system of        one or two rings of which one or both rings—with this one or two        rings then not being aromatic—contain/s one or more heteroatoms        from the group consisting of nitrogen, oxygen and/or sulfur in        the ring, more preferably is selected from oxazepam,        pyrrolidine, piperidine, piperazine, indene, 2,3-dihydroindene        (indane), tetrahydropyran, morpholine, indoline, oxopyrrolidine,        benzodioxane, especially is benzodioxane, morpholine,        tetrahydropyran, piperidine, oxopyrrolidine, and pyrrolidine.

Preferably in the context of this invention heterocyclyl is defined as aheterocyclic ring system of one or more saturated or unsaturated ringsof which at least one ring contains one or more heteroatoms from thegroup consisting of nitrogen, oxygen and/or sulfur in the ring.Preferably it is a heterocyclic ring system of one or two saturated orunsaturated rings of which at least one ring contains one or moreheteroatoms from the group consisting of nitrogen, oxygen and/or sulfurin the ring.

Preferred examples of heterocyclyls include oxazepan, pyrrolidine,imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine,piperazine, indene, 2,3-dihydroindene, benzofuran, benzimidazole,indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane,morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene,benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline,isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole,benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,benzodioxane, carbazole and quinazoline, especially is pyridine,pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine,tetrahydropyrane, pyrazole, imidazole, piperidine, thiophene, indole,benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine,pyrimidine, oxazepane and pyrrolidine.

In the context of this invention oxopyrrolidine is understood as meaningpyrrolidin-2-one.

In connection with aryl (including alkyl-aryl), cycloalkyl (includingalkyl-cycloalkyl), or heterocyclyl (including alkyl-heterocyclyl),substituted is understood—unless defined otherwise—as meaningsubstitution of the ring-system of the aryl or alkyl-aryl, cycloalkyl oralkyl-cycloalkyl; heterocyclyl or alkyl-heterocyclyl by OH, SH, ═O,halogen (F, Cl, Br, I), CN, NO₂, COOH; NR_(x)R_(y), with R_(x) and R_(y)independently being either H or a saturated or unsaturated, linear orbranched, substituted or unsubstituted C₁₋₆-alkyl; a saturated orunsaturated, linear or branched, substituted or unsubstitutedC₁₋₆-alkyl; a saturated or unsaturated, linear or branched, substitutedor unsubstituted —O—C₁₋₆-alkyl (alkoxy); a saturated or unsaturated,linear or branched, substituted or unsubstituted —S—C₁₋₆-alkyl; asaturated or unsaturated, linear or branched, substituted orunsubstituted —C(O)—C₁₋₆-alkyl-group; a saturated or unsaturated, linearor branched, substituted or unsubstituted —C(O)—O—C₁₋₆-alkyl-group; asubstituted or unsubstituted aryl or alkyl-aryl; a substituted orunsubstituted cycloalkyl or alkyl-cycloalkyl; a substituted orunsubstituted heterocyclyl or alkyl-heterocyclyl.

Most preferably in connection with aryl (including alkyl-aryl),substituted is understood in the context of this invention that any aryl(including alkyl-aryl), which is substituted is substituted by one ormore of halogen (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH, —OC₁₋₄alkylbeing unsubstituted or substituted by one or more of OH or halogen (F,Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted or substituted by oneor more of OH or halogen (F, Cl, I, Br).

Most preferably in connection with cycloalkyl (includingalkyl-cycloalkyl) or heterocyclyl (including alkyl-heterocyclyl),substituted is understood in the context of this invention that anycycloalkyl and heterocyclyl which is substituted is substituted by oneor more of halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —C(O)OH,—OC₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted orsubstituted by one or more of OH or halogen (F, Cl, I, Br).

The term “leaving group” means a molecular fragment that departs with apair of electrons in heterolytic bond cleavage. Leaving groups can beanions or neutral molecules. Common anionic leaving groups are halidessuch as Cl—, Br—, and I—, and sulfonate esters, such as tosylate (TsO—).

The term “salt” is to be understood as meaning any form of the activecompound used according to the invention in which it assumes an ionicform or is charged and is coupled with a counter-ion (a cation or anion)or is in solution. By this are also to be understood complexes of theactive compound with other molecules and ions, in particular complexeswhich are complexed via ionic interactions.

The term “physiologically acceptable salt” means in the context of thisinvention any salt that is physiologically tolerated (most of the timemeaning not being toxic-especially not caused by the counter-ion) ifused appropriately for a treatment especially if used on or applied tohumans and/or mammals.

These physiologically acceptable salts can be formed with cations orbases and in the context of this invention is understood as meaningsalts of at least one of the compounds used according to theinvention—usually a (deprotonated) acid—as an anion with at least one,preferably inorganic, cation which is physiologicallytolerated—especially if used on humans and/or mammals. The salts of thealkali metals and alkaline earth metals are particularly preferred, andalso those with NH₄, but in particular (mono)- or (di)sodium, (mono)- or(di)potassium, magnesium or calcium salts.

Physiologically acceptable salts can also be formed with anions or acidsand in the context of this invention is understood as meaning salts ofat least one of the compounds used according to the invention as thecation with at least one anion which are physiologicallytolerated—especially if used on humans and/or mammals.

By this is understood in particular, in the context of this invention,the salt formed with a physiologically tolerated acid, that is to saysalts of the particular active compound with inorganic or organic acidswhich are physiologically tolerated—especially if used on humans and/ormammals. Examples of physiologically tolerated salts of particular acidsare salts of: hydrochloric acid, hydrobromic acid, sulfuric acid,methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid or citric acid.

The compounds of the invention may be present in crystalline form or inthe form of free compounds like a free base or acid.

Any compound that is a solvate of a compound according to the inventionlike a compound according to general formula I defined above isunderstood to be also covered by the scope of the invention. Methods ofsolvation are generally known within the art. Suitable solvates arepharmaceutically acceptable solvates. The term “solvate” according tothis invention is to be understood as meaning any form of the activecompound according to the invention in which this compound has attachedto it via non-covalent binding another molecule (most likely a polarsolvent). Especially preferred examples include hydrates andalcoholates, like methanolates or ethanolates.

Any compound that is a prodrug of a compound according to the inventionlike a compound according to general formula I defined above isunderstood to be also covered by the scope of the invention. The term“prodrug” is used in its broadest sense and encompasses thosederivatives that are converted in vivo to the compounds of theinvention. Such derivatives would readily occur to those skilled in theart, and include, depending on the functional groups present in themolecule and without limitation, the following derivatives of thepresent compounds: esters, amino acid esters, phosphate esters, metalsalts sulfonate esters, carbamates, and amides.

Examples of well known methods of producing a prodrug of a given actingcompound are known to those skilled in the art and can be found e.g. inKrogsgaard-Larsen et al. “Textbook of Drug design and Discovery” Taylor& Francis (April 2002).

Unless otherwise stated, the compounds of the invention are also meantto include compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonor of a nitrogen by ¹⁵N-enriched nitrogen are within the scope of thisinvention.

The compounds of formula (I) as well as their salts or solvates of thecompounds are preferably in pharmaceutically acceptable or substantiallypure form. By pharmaceutically acceptable form is meant, inter alia,having a pharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

Purity levels for the drug substance are preferably above 50%, morepreferably above 70%, most preferably above 90%. In a preferredembodiment it is above 95% of the compound of formula (I) or, or of itssalts. This applies also to its solvates or prodrugs.

In a preferred embodiment of the compound according to the inventionaccording to general formula I

while being either substituted on one of W, X, Y or Z by

or being fused at W and X to a further ringsystem to the 5-memberedheterocyclic ring formed by W—X—Y—Z while being otherwiseunsubstituted—is selected from:

In another embodiment of the invention in the compound according to theinvention according to formula I,

can also form together with the substituent

the following unsubstituted ring system:

In another preferred embodiment of the compound according to theinvention according to general formula I

while being either substituted on one of W, X, Y or Z by

or being fused at W and X to a further ringsystem to the 5-memberedheterocyclic ring formed by W—X—Y—Z while being otherwiseunsubstituted—is selected from

In another preferred embodiment of the compound according to theinvention according to general formula I

while being either substituted on one of W, X, Y or Z by

or being fused at W and X to a further ringsystem to the 5-memberedheterocyclic ring formed by W—X—Y—Z while being otherwiseunsubstituted—is selected from

In a further preferred embodiment of the compound according to theinvention according to general formula I the compound is a compoundaccording to Formula II,

wherein

m is 1 or 2;

n is 0 or 1;

one of V¹, V³, V⁴ and V⁵ is selected from nitrogen or carbon while theothers are carbon;

R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸, —SR⁶,—S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or unsubstituted aryl andsubstituted or unsubstituted heterocyclyl;

R² is hydrogen, halogen (F, Cl, I, Br), —NR⁶R⁷, —SR⁶, —OR⁶, substitutedor unsubstituted alkyl, substituted of unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl and substituted orunsubstituted heterocyclyl; or

R¹ and R² are bonded to neighbouring atoms in the ring and together withthese atoms form a saturated or unsaturated, substituted orunsubstituted ring, fused to the ring

of the corestructure of formula II, which may be condensed with afurther unsubstituted or substituted ring system;

R³ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl and substitutedor unsubstituted heterocyclyl; and

R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted ofunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted of unsubstituted aryland substituted of unsubstituted heterocyclyl;

R⁵ is hydrogen, hydroxy, or CH₃;

R⁶, R⁷ and R⁸ are independent from each other and selected from thegroup formed by hydrogen, substituted or unsubstituted alkyl,substituted of unsubstituted cycloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl and substituted or unsubstituted heterocyclyl, or R⁶,R⁷ or R⁸ together with their respective connecting carbon or nitrogenatom may form a cycloalkylic or heterocyclic 4 to 7-membered ring;

and wherein W, X, Y and Z are selected from carbon, nitrogen, or oxygenwhile W—X—Y—Z are forming together with the bridging C-atom, that isconnected to the core scaffold, a 5-membered heterocyclic ring;

and wherein

is selected from

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In one embodiment one or more of the following provisos apply:

with the following provisos applying:

-   -   with the proviso that if V¹, V³, V⁴ and V⁵ are carbon and any of        W, X, Y or Z is

then R¹ may not be —OCH₃;

-   -   and/or    -   with the proviso that if V¹, V³, V⁴ and V⁵ are carbon, n is 0        and R³ is —CH₃ or —C₂H₅, then R¹ may not be —NH₂.

In a preferred embodiment of the compound according to the inventionaccording to general formula II

is selected from:

In another preferred embodiment of the compound according to theinvention according to general formula II

is selected from

In another embodiment of the invention in the compound according to theinvention according to Formula II,

can also form the following unsubstituted ring system

In another preferred embodiment of the compound according to theinvention according to general formulas I or II the compound is acompound according to Formula III,

wherein

m is 1 or 2;

n is 0 or 1;

V¹ is selected from nitrogen or carbon;

R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸, —SR⁶,—S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or unsubstituted aryl andsubstituted or unsubstituted heterocyclyl;

R² is hydrogen, halogen (F, Cl, I, Br), —NR⁶R⁷, —SR⁶, —OR⁶, substitutedor unsubstituted alkyl, substituted of unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl and substituted orunsubstituted heterocyclyl; or

R¹ and R² are bonded to neighbouring atoms in the ring and together withthese atoms form a saturated or unsaturated, substituted orunsubstituted ring, fused to the ring

of the corestructure of formula III, which may be condensed with afurther unsubstituted or substituted ring system;

R³ is substituted or unsubstituted alkyl, CONR⁶R⁷, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted aryland substituted or unsubstituted heterocyclyl;

R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted ofunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted of unsubstituted aryland substituted of unsubstituted heterocyclyl;

R⁵ is hydrogen, hydroxy, or CH₃;

R⁶, R⁷ and R⁸ are independent from each other and selected from thegroup formed by hydrogen, substituted or unsubstituted alkyl,substituted of unsubstituted cycloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl and substituted or unsubstituted heterocyclyl, or R⁶,R⁷ or R⁸ together with their respective connecting carbon or nitrogenatom may form a cycloalkylic or heterocyclic 4 to 7-membered ring;

and

is selected from:

and wherein

is selected from

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In one embodiment one or more of the following provisos apply:

-   -   with the proviso that if V¹ is carbon and

is

with n=0 and R³ being —CH₃ or O₂H₅, then R¹ may not be OCH₃:

-   -   and/or    -   with the proviso that if V1 is carbon, n is 0 and R³ is —CH₃ or        —O₂H₅, then R¹ may not be —NH₂.

In a preferred embodiment of the compound according to the inventionaccording to general formula III

is selected from:

In another preferred embodiment of the compound according to theinvention according to general formulas I or II the compound is acompound according to Formula IV,

wherein

m is 1 or 2;

n is 0 or 1;

V¹ is selected from nitrogen or carbon;

R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸, —SR⁶,—S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or unsubstituted aryl andsubstituted or unsubstituted heterocyclyl;

R² is hydrogen, halogen (F, Cl, I, Br), —NR⁶R⁷, —SR⁶, —OR⁶, substitutedor unsubstituted alkyl, substituted of unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl and substituted orunsubstituted heterocyclyl;

or

R¹ and R² are bonded to neighbouring atoms in the ring and together withthese atoms form a saturated or unsaturated, substituted orunsubstituted ring, fused to the ring

of the corestructure of formula IV, which may be condensed with afurther unsubstituted or substituted ring system;

R³ is substituted or unsubstituted alkyl, CONR⁶R⁷, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted aryland substituted or unsubstituted heterocyclyl;

R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted ofunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted of unsubstituted aryland substituted of unsubstituted heterocyclyl;

R⁵ is hydrogen, hydroxy, or CH₃;

R⁶, R⁷ and R⁸ are independent from each other and selected from thegroup formed by hydrogen, substituted or unsubstituted alkyl,substituted of unsubstituted cycloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl and substituted or unsubstituted heterocyclyl, or R⁶,R⁷ or R⁸ together with their respective connecting carbon or nitrogenatom may form a cycloalkylic or heterocyclic 4 to 7-membered ring;

and W, Y and Z are independently from one another selected from N or CHwith only 1 or 2 of them being CH;

and wherein

is selected from

-   -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.

In one embodiment the following proviso applies:

-   -   with the proviso that if V¹ is carbon, 2 of W, Y and Z are CH, n        is 0 and R³ is —CH₃ or —C₂H₅, then R¹ may not be —NH₂.

In a preferred embodiment of the compound according to the inventionaccording to general formula IV above

is selected from:

In a preferred embodiment of the compound according to the inventionaccording to general formula IV above the compound is a compoundaccording to Formula IV, wherein

-   -   R³ is CONR⁶R⁷, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl and        substituted or unsubstituted heterocyclyl, preferably is        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl.

In another preferred embodiment of the compound according to theinvention according to general formulas I or II the compound is acompound according to Formula V

-   -   wherein    -   m is 1 or 2;    -   n is 0 or 1;    -   V¹ is selected from nitrogen or carbon;    -   R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸,        —SR⁶, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl;    -   R² is hydrogen, halogen (F, Cl, I, Br), —NR⁶R⁷, —SR⁶, —OR⁶,        substituted or unsubstituted alkyl, substituted of unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl and        substituted or unsubstituted heterocyclyl;    -   or    -   R¹ and R² are bonded to neighbouring atoms in the ring and        together with these atoms form a saturated or unsaturated,        substituted or unsubstituted ring, fused to    -   the ring

of the corestructure of formula IV, which may be condensed with afurther unsubstituted or substituted ring system;

-   -   R³ is substituted or unsubstituted alkyl, CONR⁶R⁷, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl;    -   R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted        of unsubstituted cycloalkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted of        unsubstituted aryl and substituted of unsubstituted        heterocyclyl;    -   R⁵ is hydrogen, hydroxy, or CH₃;    -   R⁶, R⁷ and R⁸ are independent from each other and selected from        the group formed by hydrogen, substituted or unsubstituted        alkyl, substituted of unsubstituted cycloalkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl and substituted or        unsubstituted heterocyclyl, or R⁶, R⁷ or R⁸ together with their        respective connecting carbon or nitrogen atom may form a        cycloalkylic or heterocyclic 4 to 7-membered ring;    -   and wherein

is selected from

-   -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I or II the compound is acompound according to Formula V (with the preferred substituents)

-   -   wherein    -   m is 1 or 2;    -   n is 0 or 1;    -   V¹ is selected from nitrogen or carbon;    -   R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸,        —SR⁶, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl;    -   R² is hydrogen, halogen, —NR⁶R⁷, —SR⁶, —OR⁶, substituted or        unsubstituted alkyl, substituted of unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl and        substituted or unsubstituted heterocyclyl;    -   or    -   R¹ and R² are bonded to neighbouring atoms in the ring and        together with these atoms form a saturated or unsaturated,        substituted or unsubstituted ring, fused to    -   the ring

-   -    of the corestructure of formula IV, which may be condensed with        a further unsubstituted or substituted ring system;        -   wherein said aryl in R¹ and/or in R², or said ring formed by            R¹ and R² or the ring condensed to it, if a substituted            aryl, is substituted with one or more substituents selected            from halogen (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH,            —OC₁₋₄alkyl being unsubstituted or substituted by one or            more of OH or halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl            being unsubstituted or substituted by one or more of OH or            halogen (F, Cl, I, Br);        -   wherein said heterocyclyl in R¹ and/or said heterocyclyl or            cycloalkyl in R², or said ring formed by R¹ and R² or the            ring condensed to it, if a substituted heterocyclyl or            cycloalkyl, is substituted with one or more substituents            selected from halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O,            —C(O)OH, —OC₁₋₄alkyl being unsubstituted or substituted by            one or more of OH or halogen (F, Cl, I, Br), —CN, or            —C₁₋₄alkyl being unsubstituted or substituted by one or more            of OH or halogen (F, Cl, I, Br);        -   wherein said alkyl, alkenyl or alkynyl in R², if            substituted, is substituted with one or more substituents            selected from F, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or            —OC₁₋₄alkyl being unsubstituted or substituted by one or            more of OH or halogen (F, Cl, I, Br);    -   R³ is substituted or unsubstituted alkyl, CONR⁶R⁷, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl;    -   R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted        of unsubstituted cycloalkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted of        unsubstituted aryl and substituted of unsubstituted        heterocyclyl;        -   wherein said aryl in R³ and/or in R⁴, if a substituted aryl,            is substituted with one or more substituents selected from            halogen (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH, —OC₁₋₄alkyl            being unsubstituted or substituted by one or more of OH or            halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl being            unsubstituted or substituted by one or more of OH or halogen            (F, Cl, I, Br);        -   wherein said heterocyclyl or cycloalkyl in in R³ and/or in            R⁴, if a substituted heterocyclyl or cycloalkyl, is            substituted with one or more substituents selected from            halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —C(O)OH,            —OC₁₋₄alkyl being unsubstituted or substituted by one or            more of OH or halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl            being unsubstituted or substituted by one or more of OH or            halogen (F, Cl, I, Br);        -   wherein said alkyl, alkenyl or alkynyl in R³ and/or in R⁴,            if substituted, is substituted with one or more substituents            selected from F, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or            —OC₁₋₄alkyl being unsubstituted or substituted by one or            more of OH or halogen (F, Cl, I, Br);    -   R⁵ is hydrogen, hydroxy, or CH₃;    -   R⁶, R⁷ and R⁸ are independent from each other and selected from        the group formed by hydrogen, substituted or unsubstituted        alkyl, substituted of unsubstituted cycloalkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl and substituted or        unsubstituted heterocyclyl, or R⁶, R⁷ or R⁸ together with their        respective connecting carbon or nitrogen atom may form a        cycloalkylic or heterocyclic 4 to 7-membered ring;        -   wherein said aryl in R⁶, in R⁷, and/or in R⁸, if a            substituted aryl, is substituted with one or more            substituents selected from halogen (F, Cl, I, Br), —OH,            —NH₂, —SH, —C(O)OH, —OC₁₋₄alkyl being unsubstituted or            substituted by one or more of OH or halogen (F, Cl, I, Br),            —CN, or —C₁₋₄alkyl being unsubstituted or substituted by one            or more of OH or halogen (F, Cl, I, Br);        -   wherein said heterocyclyl or cycloalkyl in in R⁶, in R⁷,            and/or in R⁸, if a substituted heterocyclyl or cycloalkyl,            is substituted with one or more substituents selected from            halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —C(O)OH,            —OC₁₋₄alkyl being unsubstituted or substituted by one or            more of OH or halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl            being unsubstituted or substituted by one or more of OH or            halogen (F, Cl, I, Br);        -   wherein said alkyl, alkenyl or alkynyl in R⁶, in R⁷, and/or            in R⁸, if substituted, is substituted with one or more            substituents selected from F, Cl, Br, I, NH₂, SH or OH,            —C(O)OH, or —OC₁₋₄alkyl being unsubstituted or substituted            by one or more of OH or halogen (F, Cl, I, Br);    -   and W, Y and Z are independently from one another selected from        N or CH with only 1 or 2 of them being CH;

and wherein

is selected from

-   -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof;    -   with the following proviso applying:        -   with the proviso that if V¹ is carbon, 2 of W, Y and Z are            CH, n is 0 and R³ is —CH₃ or —O₂H₅, then R¹ may not be —NH₂.

In another preferred embodiment of the compound according to theinvention according to general formula V the compound is selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)ethanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   1,1,1-trifluoro-N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(4-((1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-((1R,5S)-3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)methanesulfonamide,-   N-(3-(4-((2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(6-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,-   3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)aniline,-   N-tert-butyl-3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)benzenesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)methanesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propionamide,-   N-(6-(4-((1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(5-chloro-6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,    and-   N-(6-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another very preferred embodiment of the compound according to theinvention according to general formulas I, II, III, or IV the compoundis selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)ethanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(4-((1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-((1R,5S)-3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)methanesulfonamide,-   N-(3-(4-((2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(6-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,-   N-tert-butyl-3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)benzenesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)methanesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propionamide,-   N-(6-(4-((1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(5-chloro-6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,    and-   N-(6-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, or IV the compoundis selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)ethanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(6-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)methanesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(6-(4-((1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(5-chloro-6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,    and-   N-(6-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another highly preferred embodiment of the compound according to theinvention according to general formulas I, II, III, or IV the compoundis selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,    and-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸,        —SR⁶, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl, wherein        -   the aryl is selected from phenyl, naphtyl, or anthracene;            preferably is napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring, more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline;        -   and/or        -   most preferably R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷,            —NR⁶COR⁷, NR⁶CONR⁷R⁸, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷,            substituted or unsubstituted aryl like phenyl and            substituted or unsubstituted heterocyclyl like imidazol;    -   and/or    -   R² is hydrogen, halogen (F, Cl, I, Br), —NR⁶R⁷, —SR⁶, —OR⁶,        substituted or unsubstituted alkyl, substituted of unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl and        substituted or unsubstituted heterocyclyl, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl;        -   and/or        -   halogen is any of fluorine, chlorine, iodine or bromine,            preferably chlorine or fluorine;        -   and/or        -   most preferably R² is selected from hydrogen, halogen like            fluorine, or C₁₋₄alkyl like CH₃ or CF₃;    -   and/or    -   R¹ and R² are bonded to neighbouring atoms in the ring and        together with these atoms form a saturated or unsaturated,        substituted or unsubstituted ring, fused to the ring

or J of the corestructure of formulas I, II, III, IV, or V respectively,which may be condensed with a further unsubstituted or substituted ringsystem, wherein

-   -   the ring is either unsubstituted or substituted by one or more        of halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br), —CN, or C₁₋₄alkyl being unsubstituted or substituted        by one or more of OH or halogen (F, Cl, I, Br); preferably the        ring being formed with V¹, V², V³, V⁴ and V⁵ all being carbon is        fused with a phenyl ring on the corestructure

forming a double ring, more preferably forming a heterocyclic doublering, most preferably the heterocyclic double ring formed by R¹ and R²with the corestructure is selected from benzoimidazole, indazole,indoline and benzothiazole being unsubstituted or being substituted byone or more of halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —OC₁₋₄alkylbeing unsubstituted or substituted by one or more of OH or halogen (F,Cl, I, Br), —CN, or C₁₋₄alkyl being unsubstituted or substituted by oneor more of OH or halogen (F, Cl, I, Br);

-   -   and/or    -   R³ is substituted or unsubstituted alkyl, CONR⁶R⁷, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline,            especially is pyridine, imidazole, indene,            2,3-dihydroindene, benzofuran, pyrimidine;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl            or R³ is not alkyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl, especially cyclopentyl or            cyclohexyl;        -   and/or        -   preferably R³ is not alkyl;        -   and/or        -   most preferably R³ is selected from substituted or            unsubstituted alkyl like propyl or butyl, CONR⁶R⁷ like            diethylacetamide, from substituted or unsubstituted            cycloalkyl like cyclopentyl or cyclohexyl, or from            substituted or unsubstituted aryl, like phenyl, or from            substituted or unsubstituted heterocyclyl, like pyridine,            imidazole, indene, 2,3-dihydroindene, benzofuran,            pyrimidine,        -   or most preferably R³ is selected from substituted or            unsubstituted cycloalkyl like cyclopentyl or cyclohexyl, or            from substituted or unsubstituted aryl, like phenyl, or from            substituted or unsubstituted heterocyclyl, like pyridine,            imidazole, indene, 2,3-dihydroindene, benzofuran,            pyrimidine;    -   and/or    -   R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted        of unsubstituted cycloalkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted of        unsubstituted aryl and substituted of unsubstituted        heterocyclyl, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline,            especially is pyridine, imidazole, indene,            2,3-dihydroindene, benzofuran, pyrimidine;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl, especially cyclopentyl or            cyclohexyl;        -   and/or        -   most preferably R⁴ is selected from hydrogen or from            substituted or unsubstituted C₁₋₄alkyl like CH₃ or CH₂OH;    -   and/or    -   R⁵ is hydrogen, hydroxy, or CH₃, or is only hydrogen or CH₃;    -   and/or    -   R⁶, R⁷ and R⁸ are independent from each other and selected from        the group formed by hydrogen, substituted or unsubstituted        alkyl, substituted of unsubstituted cycloalkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl and substituted or        unsubstituted heterocyclyl, or R⁶, R⁷ or R⁸ together with their        respective connecting carbon or nitrogen atom may form a        cycloalkylic or heterocyclic 4 to 7-membered ring, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the alkyl-aryl is C₁₋₄-alkyl-aryl; preferably is benzyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline,            especially is pyridine, imidazole, indene,            2,3-dihydroindene, benzofuran, pyrimidine;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl, especially cyclopentyl or            cyclohexyl;        -   and/or        -   when R⁶, R⁷ or R⁸ together with their respective connecting            carbon or nitrogen atom form a cycloalkylic or heterocyclic            ring this ring is 5 or 6 membered, preferably form a            saturated cycloalkylic ring of 5 or 6 members, like            saturated, unsubstituted cyclohexyl;        -   and/or        -   most preferably R⁶, R⁷, and R⁸ are independently from each            other selected from hydrogen, from substituted or            unsubstituted C₁₋₄alkyl like methyl, ethyl, propyl or butyl,            from substituted or unsubstituted aryl like phenyl, from            substituted or unsubstituted heterocyclyl like pyrrolidine,            or from substituted or unsubstituted alkyl-aryl like benzyl,            or R⁶ and R⁷ together with their connecting carbon atom form            a cycloalkylic 5 or 6-membered ring like cyclohexyl.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸,        —SR⁶, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or        unsubstituted aryl and substituted or unsubstituted        heterocyclyl, wherein        -   the aryl is selected from phenyl, naphtyl, or anthracene;            preferably is napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring, more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline;        -   and/or        -   most preferably R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷,            —NR⁶COR⁷, NR⁶CONR⁷R⁸, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷,            substituted or unsubstituted aryl like phenyl and            substituted or unsubstituted heterocyclyl like imidazol.    -   In another preferred embodiment of the compound according to the        invention according to general formulas I, II, III, IV or V the        compound is a compound, wherein R² is hydrogen, halogen (F, Cl,        I, Br), —NR⁶R⁷, —SR⁶, —OR⁶, substituted or unsubstituted alkyl,        substituted of unsubstituted cycloalkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl and substituted or        unsubstituted heterocyclyl, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl;        -   and/or        -   halogen is any of fluorine, chlorine, iodine or bromine,            preferably chlorine or fluorine;        -   and/or        -   most preferably R² is selected from hydrogen, halogen like            fluorine, or C₁₋₄alkyl like CH₃ or CF₃.    -   In another preferred embodiment of the compound according to the        invention according to general formulas I, II, III, IV or V the        compound is a compound, wherein R¹ and R² are bonded to        neighbouring atoms in the ring and together with these atoms        form a saturated or unsaturated, substituted or unsubstituted        ring, fused to the ring

of the corestructure of formulas I, II, III, IV or V respectively, whichmay be condensed with a further unsubstituted or substituted ringsystem, wherein

-   -   the ring is either unsubstituted or substituted by one or more        of halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —OC₁₋₄alkyl being        unsubstituted or substituted by one or more of OH or halogen (F,        Cl, I, Br), —CN, or C₁₋₄alkyl being unsubstituted or substituted        by one or more of OH or halogen (F, Cl, I, Br); preferably the        ring being formed with V¹, V², V³, V⁴ and V⁵ all being carbon is        fused with a phenyl ring on the corestructure

forming a double ring, more preferably forming a heterocyclic doublering, most preferably the heterocyclic double ring formed by R¹ and R²with the corestructure is selected from benzoimidazole, indazole,indoline and benzothiazole being unsubstituted or being substituted byone or more of halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —OC₁₋₄alkylbeing unsubstituted or substituted by one or more of OH or halogen (F,Cl, I, Br), —CN, or C₁₋₄alkyl being unsubstituted or substituted by oneor more of OH or halogen (F, Cl, I, Br).

-   -   In another preferred embodiment of the compound according to the        invention according to general formulas I, II, III, IV or V the        compound is a compound, wherein R³ is substituted or        unsubstituted alkyl, CONR⁶R⁷, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl and        substituted or unsubstituted heterocyclyl, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline,            especially is pyridine, imidazole, indene,            2,3-dihydroindene, benzofuran, pyrimidine;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl            or R³ is not alkyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl, especially cyclopentyl or            cyclohexyl;        -   and/or        -   preferably R³ is not alkyl;        -   and/or        -   most preferably R³ is selected from substituted or            unsubstituted alkyl like propyl or butyl, CONR⁶R⁷ like            diethylacetamide, from substituted or unsubstituted            cycloalkyl like cyclopentyl or cyclohexyl, or from            substituted or unsubstituted aryl, like phenyl, or from            substituted or unsubstituted heterocyclyl, like pyridine,            imidazole, indene, 2,3-dihydroindene, benzofuran,            pyrimidine,        -   or most preferably R³ is selected from substituted or            unsubstituted cycloalkyl like cyclopentyl or cyclohexyl, or            from substituted or unsubstituted aryl, like phenyl, or from            substituted or unsubstituted heterocyclyl, like pyridine,            imidazole, indene, 2,3-dihydroindene, benzofuran,            pyrimidine.    -   In another preferred embodiment of the compound according to the        invention according to general formulas I, II, III, IV or V the        compound is a compound, wherein R⁴ is hydrogen, substituted or        unsubstituted alkyl, substituted of unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted of unsubstituted aryl and        substituted of unsubstituted heterocyclyl, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline,            especially is pyridine, imidazole, indene,            2,3-dihydroindene, benzofuran, pyrimidine;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl, especially cyclopentyl or            cyclohexyl;        -   and/or        -   most preferably R⁴ is selected from hydrogen or from            substituted or unsubstituted C₁₋₄alkyl like CH₃ or CH₂OH.    -   In another preferred embodiment of the compound according to the        invention according to general formulas I, II, III, IV or V the        compound is a compound, wherein R⁵ is hydrogen, hydroxy, or CH₃,        or is only hydrogen or CH₃.    -   In another preferred embodiment of the compound according to the        invention according to general formulas I, II, III, IV or V the        compound is a compound, wherein R⁶, R⁷ and R⁸ are independent        from each other and selected from the group formed by hydrogen,        substituted or unsubstituted alkyl, substituted of unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl and        substituted or unsubstituted heterocyclyl, or R⁶, R⁷ or R⁸        together with their respective connecting carbon or nitrogen        atom may form a cycloalkylic or heterocyclic 4 to 7-membered        ring, wherein        -   the aryl is phenyl, naphtyl or anthracene; preferably is            napthyl and phenyl; more preferably is phenyl;        -   and/or        -   the alkyl-aryl is C₁₋₄-alkyl-aryl; preferably is benzyl;        -   and/or        -   the heterocyclyl is a heterocyclic ring system of one or            more saturated or unsaturated rings of which at least one            ring contains one or more heteroatoms from the group            consisting of nitrogen, oxygen and/or sulfur in the ring;            preferably is a heterocyclic ring system of one or two            saturated or unsaturated rings of which at least one ring            contains one or more heteroatoms from the group consisting            of nitrogen, oxygen and/or sulfur in the ring; more            preferably is selected from imidazole, oxadiazole,            tetrazole, pyridine, pyrimidine, piperidine, indene,            2,3-dihydroindene, benzofuran, benzimidazole, indazole,            benzothiazole, indoline, furan, triazole, isoxazole,            pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,            quinoline, isoquinoline, phthalazine,            benzo-1,2,5-thiadiazole, indole, benzotriazole,            benzodioxolane, benzodioxane, carbazole and quinazoline,            especially is pyridine, imidazole, indene,            2,3-dihydroindene, benzofuran, pyrimidine;        -   and/or        -   the alkyl is C₁₋₈alkyl like methyl, ethyl, propyl, butyl,            pentyl, hexyl, heptyl, or octyl; preferably is C₁₋₆alkyl            like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more            preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl;        -   and/or        -   the alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl like ethylene,            propylene, butylene, pentylene, hexylene, heptylene or            octylene; preferably id C₁₋₆-alkenyl like ethylene,            propylene, butylene, pentylene, or hexylene; more preferably            from C₁₋₄-alkenyl, like ethylene, propylene, or butylene;        -   and/or        -   the alkynyl is C₂₋₁₀-alkynyl or C₂₋₈-alkynyl like ethyne,            propyne, butyene, pentyne, hexyne, heptyne, or octyne;            preferably is C₂₋₆-alkynyl like ethyne, propyne, butyene,            pentyne, or hexyne; more preferably is C₂₋₄-alkynyl like            ethyne, propyne, butyene, pentyne, or hexyne;        -   and/or        -   the cycloalkyl is C₃₋₈cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or            cyclooctyl; preferably is C₃₋₇cycloalkyl like cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more            preferably from C₃₋₆cycloalkyl like cyclopropyl, cyclobutyl,            cyclopentyl or cyclohexyl, especially cyclopentyl or            cyclohexyl;        -   and/or        -   when R⁶, R⁷ or R⁸ together with their respective connecting            carbon or nitrogen atom form a cycloalkylic or heterocyclic            ring this ring is 5 or 6 membered, preferably form a            saturated cycloalkylic ring of 5 or 6 members, like            saturated, unsubstituted cyclohexyl;        -   and/or        -   most preferably R⁶, R⁷, and R⁸ are independently from each            other selected from hydrogen, from substituted or            unsubstituted C₁₋₄alkyl like methyl, ethyl, propyl or butyl,            from substituted or unsubstituted aryl like phenyl, from            substituted or unsubstituted heterocyclyl like pyrrolidine,            or from substituted or unsubstituted alkyl-aryl like benzyl,            or R⁶ and R⁷ together with their connecting carbon atom form            a cycloalkylic 5 or 6-membered ring like cyclohexyl.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   m is 1 or 2;    -   n is 0 or 1;    -   V¹ is selected from nitrogen or carbon;    -   R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸,        —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or unsubstituted        aryl and substituted or unsubstituted heterocyclyl;    -   R² is hydrogen, halogen like fluorine, or C₁₋₄alkyl like CH₃ or        CF₃, preferably is hydrogen;    -   or    -   R¹ and R² form a heterocyclic double ring with the        corestructure, preferably being selected from benzoimidazole,        indazole, indoline and benzothiazole being unsubstituted or        being substituted by one or more of halogen (F, Cl, I, Br), —OH,        —NH₂, —SH, ═O, —OC₁₋₄alkyl being unsubstituted or substituted by        one or more of OH or halogen (F, Cl, I, Br), —CN, or C₁₋₄alkyl        being unsubstituted or substituted by one or more of OH or        halogen (F, Cl, I, Br);    -   R³ is selected from substituted or unsubstituted cycloalkyl like        cyclopentyl or cyclohexyl, or from substituted or unsubstituted        aryl, like phenyl, or from substituted or unsubstituted        heterocyclyl, like pyridine, imidazole, indene,        2,3-dihydroindene, benzofuran, pyrimidine;    -   R⁴ is hydrogen or substituted or unsubstituted C₁₋₄alkyl like        CH₃ or CH₂OH;    -   R⁵ is hydrogen, hydroxy, or CH₃, preferably hydrogen;    -   R⁶, R⁷, and R⁸ are independently from each other selected from        hydrogen, from substituted or unsubstituted C₁₋₄alkyl like        methyl, ethyl, propyl, isopropyl, tert-butyl or butyl, from        substituted or unsubstituted aryl like phenyl, from substituted        or unsubstituted heterocyclyl like pyrrolidine, or from        substituted or unsubstituted alkyl-aryl like benzyl, or R⁶ and        R⁷ together with their connecting carbon atom form a        cycloalkylic 5 or 6-membered ring like cyclohexyl.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   m is 1.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   n is 0 or 1.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   V¹ is selected from nitrogen and carbon.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R¹ is hydroxyl, —NH₂, —NHS(O)₂-isopropyl, —NHS(O)₂-methyl,        —NHS(O)₂-ethyl, —NHS(O)₂-cyclopropyl, —NHS(O)₂—CF₃,        —S(O)₂NH-tert-butyl, NHC(O)-ethyl.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R² is hydrogen.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R³ is selected from substituted or unsubstituted phenyl and from        substituted or unsubstituted pyrimidine.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R⁴ is hydrogen.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R⁵ is hydrogen.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R⁶ is hydrogen.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, IV or V the compoundis a compound, wherein

-   -   R⁷ is hydrogen, substituted or unsubstituted methyl, substituted        or unsubstituted ethyl, substituted or unsubstituted isopropyl,        substituted or unsubstituted tert-butyl, substituted or        unsubstituted cyclopropyl or —CF₃.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II or III the compound is acompound, wherein

is substituted triazole, substituted pyrazole or substituted imidazole,preferably selected from

In another preferred embodiment of the compound according to theinvention according to general formulas I, II or III, IV or V thecompound is a compound, wherein

is selected from

In another very preferred embodiment of the compound according to theinvention according to general Formula IV, the compound is a compound,wherein

-   -   m is 1 or 2;    -   n is 0 or 1;    -   V¹ is selected from nitrogen or carbon;    -   R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸,        —S(O)₂R⁶, —S(O)₂NR⁶R⁷, —CONR⁶R⁷, substituted or unsubstituted        phenyl and substituted or unsubstituted imidazol, preferably is        hydroxyl, NR⁶R⁷, S(O)₂NR⁶R⁷, NR⁶COR⁷ and —NR⁶S(O)₂R⁷;    -   R² is hydrogen;    -   or    -   R³ is selected from substituted or unsubstituted cyclopentyl,        cyclohexyl, or from substituted or unsubstituted phenyl, or from        substituted or unsubstituted heterocyclyl, like pyridine,        imidazole, indene, 2,3-dihydroindene, benzofuran, pyrimidine;        preferably is phenyl or pyridine;    -   R⁴ is hydrogen or substituted or unsubstituted C₁₋₄alkyl,        preferably is hydrogen;    -   R⁵ is hydrogen, hydroxy, or CH₃, preferably is hydrogen or CH₃,        more preferably hydrogen;    -   R⁶, R⁷ and R⁸ are independent from each other and selected from        the group formed by hydrogen, substituted or unsubstituted        alkyl, substituted of unsubstituted cycloalkyl, substituted or        unsubstituted phenyl, preferably are selected from hydrogen,        substituted or unsubstituted C₁₋₄alkyl, substituted of        unsubstituted C₃₋₆cycloalkyl;    -   and W, Y and Z are independently from one another selected from        N or CH with only 1 or 2 of them being CH;    -   and wherein

is selected from

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, or IV the compoundis selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(6-(trifluoromethyl)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)ethanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   1,1,1-trifluoro-N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(4-((1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-((1R,5S)-3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)methanesulfonamide,-   N-(3-(4-((2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(6-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,-   3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)aniline,-   N-tert-butyl-3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)benzenesulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-benzyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-benzyl-1H-imidazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)methanesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propionamide,-   N-(6-(4-((1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(5-chloro-6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,    and-   N-(6-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another very preferred embodiment of the compound according to theinvention according to general formulas I, II, III, or IV the compoundis selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)ethanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(4-((1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-((1R,5S)-3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)methanesulfonamide,-   N-(3-(4-((2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(6-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,-   N-tert-butyl-3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)benzenesulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-benzyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-benzyl-1H-imidazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)methanesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propionamide,-   N-(6-(4-((1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(5-chloro-6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,    and-   N-(6-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, II, III, or IV the compoundis selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)ethanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-ylamino)phenyl)methanesulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)azetidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)phenyl)methanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(6-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-benzyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-benzyl-1H-imidazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)methanesulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(6-(4-((1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide,-   N-(5-chloro-6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide,-   N-(6-(5-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,    and-   N-(6-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide,

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another highly preferred embodiment of the compound according to theinvention according to general formulas I, II, III, or IV the compoundis selected from

-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(methyl(1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide,-   N-(3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   3-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenol,-   N-(3-(4-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)phenyl)propane-2-sulfonamide,-   and-   N-(6-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2-yl)propane-2-sulfonamide;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opiod receptor it is a very preferred embodiment in which thecompounds are selected which act as dual ligands of the σ₁ receptor andthe μ-opiod receptor and especially compounds which have a bindingexpressed as K, which is <100 nm for both receptors.

In the following the phrase “compound of the invention” is used. This isto be understood as any compound according to the invention as describedabove according to general formulas I, II, III, IV, or V.

The compounds of the invention represented by the above describedformula (I) may include enantiomers depending on the presence of chiralcentres or isomers depending on the presence of multiple bonds (e.g. Z,E). The single isomers, enantiomers or diastereoisomers and mixturesthereof fall within the scope of the present invention.

In general the processes are described below in the experimental part.The starting materials are commercially available or can be prepared byconventional methods.

A preferred aspect of the invention is also a process for the productionof a compound according to formula I,

wherein R¹, R², R⁵, V¹, V², V³, W, X, Y, Z and m as well as

are as defined in claim 1 or according to formula Ia

-   -   wherein R¹, R², R³, R⁴, R⁵, V¹, V², V³, W, X, Y, Z, n and m are        as defined in claim 1    -   wherein a compound of formula VI or its suitable salt like the        hydrochloride

-   -   wherein R¹, R², R⁵, V¹, V², and V³ are as defined for Formula I,        is reacted with a compound according to formula VII (for a        compound according to formula I) or according to formula VIIa        (for a compound according to formula Ia) under the conditions of        Step 1

-   -   wherein R³, R⁴, W, X, Y, Z and n are as defined in Formula I,        leading to a compound according to formula (I) or formula (Ia)        respectively,    -   wherein the reductive amination reaction of the compounds of        formula (VI) and (VII or VIIa) of Step 1 is carried out with a        reductive reagent in an aprotic solvent in the presence of an        organic base,

Preferably in the reaction of Step 1 above the reductive reagent issodium triacetoxyborohydride, the aprotic solvent is dichloroethaneand/or the organic base is diisopropylethylamine.

Another preferred aspect of the invention is a process for theproduction of a compound according to the invention, wherein a compoundof formula V

wherein R¹, R², R³, R⁴, R⁵, n and m as well as

are as defined in claim 7,

-   -   wherein a compound of formula VIII or its suitable salt like the        hydrochloride

-   -   wherein R¹, R², and R⁵ are as defined in claim 7, is reacted        with a compound according to formula X under the conditions of        Step 2

-   -   wherein m is as defined in claim 7, leading to a compound        according to formula IX,

-   -   wherein R¹, R², R⁵ and m are as defined in claim 7,    -   followed by reacting said compound according to formula IX with        a compound according to formula XI under the conditions of Step        3

-   -   wherein R³, R⁴ and n are as defined in claim 7, under the        conditions of Step 3, leading to a compound according to formula        (V),    -   wherein X is a leaving group like a halogen (F, Cl, I, Br) or        sulphate like chlorine,    -   wherein the reaction of Step 2 of said compounds of general        formula (VIII) with said compounds of formula (X) is carried out        in the presence of a base in an aprotic solvent.    -   wherein the reaction of Step 3 of said compounds of general        formula (IX) with said compounds of formula (XI) is carried out        in the presence of a copper salt and sodium ascorbate in a        mixture of protic organic solvent and water.

Preferably in the reaction of Step 2 above the base is Et₃N, the aproticsolvent is tetrahydrofurane (THF) and/or the reaction is preferablycarried out at a temperature range of 25-75° C. The temperature may beraised by conventional methods or by use of microwave.

Preferably in the reaction of Step 3 above the copper salt is CuSO₄.5H₂Oand the mixture of protic organic solvent and water is a mixture oft-BuOH:H₂O 1:1 and/or the reaction is preferably carried out at roomtemperature.

The obtained reaction products may, if desired, be purified byconventional methods, such as crystallisation and chromatography. Wherethe above described processes for the preparation of compounds of theinvention give rise to mixtures of stereoisomers, these isomers may beseparated by conventional techniques such as preparative chromatography.If there are chiral centers the compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form of a compound of theinvention is the crystalline form, including such form in pharmaceuticalcomposition. In the case of salts and also solvates of the compounds ofthe invention the additional ionic and solvent moieties must also benon-toxic. The compounds of the invention may present differentpolymorphic forms, it is intended that the invention encompasses allsuch forms.

Another aspect of the invention refers to a pharmaceutical compositionwhich comprises a compound according to the invention as described aboveaccording to general formulas I, II, III, IV, or V or a pharmaceuticallyacceptable salt or steroisomer thereof, and a pharmaceuticallyacceptable carrier, adjuvant or vehicle. The present invention thusprovides pharmaceutical compositions comprising a compound of thisinvention, or a pharmaceutically acceptable salt or stereoisomersthereof together with a pharmaceutically acceptable carrier, adjuvant,or vehicle, for administration to a patient.

Examples of pharmaceutical compositions include any solid (tablets,pills, capsules, granules etc.) or liquid (solutions, suspensions oremulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oralform, either solid or liquid. Suitable dose forms for oraladministration may be tablets, capsules, syrops or solutions and maycontain conventional excipients known in the art such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulfate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art. The tablets may for example be prepared by wet or drygranulation and optionally coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteraladministration, such as sterile solutions, suspensions or lyophilizedproducts in the appropriate unit dosage form. Adequate excipients can beused, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods suchas those described or referred to in the Spanish and US Pharmacopoeiasand similar reference texts.

Administration of the compounds or compositions of the present inventionmay be by any suitable method, such as intravenous infusion, oralpreparations, and intraperitoneal and intravenous administration. Oraladministration is preferred because of the convenience for the patientand the chronic character of the diseases to be treated.

Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 1, 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with otherdrugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition foradministration at the same time or at different time.

Another aspect of the invention refers to the use of a compound of theinvention or a pharmaceutically acceptable salt or isomer thereof in themanufacture of a medicament.

Another aspect of the invention refers to a compound of the inventionaccording as described above according to general formulas I, II, III,IV, or V or a pharmaceutically acceptable salt or isomer thereof, foruse as a medicament for the treatment of pain. Preferably the pain ismedium to severe pain, visceral pain, chronic pain, cancer pain,migraine, inflammatory pain, acute pain or neuropathic pain, allodyniaor hyperalgesia. This may include mechanical allodynia or thermalhyperalgesia.

Another aspect of the invention refers to the use of a compound of theinvention in the manufacture of a medicament for the treatment orprophylaxis of pain.

In a preferred embodiment the pain is selected from medium to severepain, visceral pain, chronic pain, cancer pain, migraine, inflammatorypain, acute pain or neuropathic pain, allodynia or hyperalgesia, alsopreferably including mechanical allodynia or thermal hyperalgesia.

Another aspect of this invention relates to a method of treating orpreventing pain which method comprises administering to a patient inneed of such a treatment a therapeutically effective amount of acompound as above defined or a pharmaceutical composition thereof. Amongthe pain syndromes that can be treated are medium to severe pain,visceral pain, chronic pain, chronic pain, cancer pain, migraine,inflammatory pain, acute pain or neuropathic pain, allodynia orhyperalgesia, whereas this could also include mechanical allodynia orthermal hyperalgesia.

The present invention is illustrated below with the aid of examples.These illustrations are given solely by way of example and do not limitthe general spirit of the present invention.

EXAMPLES General Experimental Part (Methods and Equipment of theSynthesis and Analysis

All solvents used for synthesis were p. a. quality.

Method I

A process is described for the preparation of compounds of generalformula (I_(ex)) where R₁, R₂, R₃, R₄, A, B, Y, Z, W, n and m have themeanings as defined above (with “A”, “B”, “Y”, and “Z” being “X”, “Y”,“W”, “Z” in the above description, respectively, and “W” being “V^(1′)”in the above description), comprising the reaction of compound offormula (II_(ex)), or its suitable salt such as hydrochloride, with acompound of general formula (III_(ex)) as described in Scheme 1. Thereductive amination reaction of compounds of formula (II_(ex)) and(III_(ex)) is preferably carried out with a reductive reagent,preferably sodium triacetoxyborohydride, in an aprotic solvent,preferably dichloroethane, in the presence of an organic base preferablydiisopropylethylamine.

Method II

A process is described for the preparation of compounds of generalformula (Ia_(ex) and Ib_(ex)) where R₁, R₂, R₃, R₄, R₅, W, n and m havethe meanings as defined above (with “W” being “V^(1′)” in the abovedescription), comprising the reaction of compound of formula (II_(ex))with a compound of formula (IV_(ex)), where X is a suitable leavinggroup such as an halogen or sulfonate, and the reaction of the resultingintermediate (V_(ex)) with convenient reagents such as (VI_(ex)),(VII_(ex)) or (VIII_(ex)) to give the triazoles (Ia_(ex)) and (Ib_(ex)).As indicated in Scheme 2, different methods can be used in the practicalrealization of these two reactions. In some cases, the intermediate(V_(ex)) can be isolated but in other cases the two steps may be carriedout one-pot. The compounds of formula (IV_(ex)) and the reagents offormula (VI_(ex)), (VII_(ex)) or (VIII_(ex)) are either commerciallyavailable or can be prepared following conventional methods reported inthe literature. Alternately, some of the azides can be prepared in situ.

In Method IIA the reaction of compounds of general formula (II_(ex))with compounds of formula (IV_(ex)) where X is a suitable leaving group,such as a halogen or sulfonate, is carried out in the presence of abase, preferably Et₃N, in an aprotic solvent such as tetrahydrofurane(THF) at a temperature range of 25-75° C., using conventional heating ora microwave reactor.

In Method IIB the reaction of compounds of formula (V_(ex)) with azidesof general formula (VI_(ex)) is carried out in the presence of a coppersalt, preferably CuSO₄.5H₂O and sodium ascorbate, in a mixture of proticorganic solvent and water, preferably a mixture of t-BuOH:H₂O 1:1 atroom temperature.

In Method IIC the azide is generated in situ. The precursor of the azide(VII_(ex)), where X is a suitable leaving group such as an halogen orsulfonate, is treated with sodium azide and a copper salt, preferablyCuI, in an organic solvent, preferably dimethylformamide, at 100° C.using microwave irradiation. Alternatively, some additives such asN₁,N₂-dimethylethane-1,2-diamine (DMEDA) and sodium ascorbate can beadded to the reaction mixture.

In Method IIID the precursor of the azide of general formula (VII_(ex))is treated with sodium azide in a mixture of a protic organic solventand water, preferably a mixture of t-BuOH:H₂O 1:1, at 100° C. usingmicrowave irradiation for a suitable time, such as 1 h or untilcompleted reaction. The in situ formed azide is then treated withcompounds of general formula (V_(ex)) in the presence of a copper salt,preferably CuSO₄.5H₂O and sodium ascorbate at room temperature.

In Method IIIE the intermediates of general formula (Ia_(ex)) areprepared in a one-pot procedure comprising the reaction of compounds ofgeneral formula (II_(ex)) and propargyl bromide in the presence of abase, preferably Et₃N, in water at room temperature for 1 h or untilcompleted reaction, after which compounds of general formula (VI_(ex))are added in the presence of a copper salt, preferably CuI, at roomtemperature (Tetrahedron 2005, 61, 9331-9337).

Additionally the compounds of formula I_(ex) can be prepared byinterconversion of functional groups present in the final molecules. Inthis, functional groups that are present on some part of the finalmolecule could be converted into other related functional groups eitherwith or without an intermediate product by inducing a chemical reaction.

Synthesis of Intermediates of General Formula (II)

In some cases, compounds of formula (II_(ex)) are commercially availableor they can be obtained by conventional methods. Alternatively, acompound of formula (II_(ex)) can be obtained following differentmethods:

Method III

Method IIIA comprises:

-   -   a) The reaction of compounds of formula (IX_(ex)) with a        compound of formula (Xa_(ex)) in the presence of a palladium        catalyst, preferably Pd(OAc), a phosphine ligand, preferably        di-tert-butyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphine,        [1,1′-biphenyl]-2-yldi-tert-butylphosphine or        ((2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)), in the presence        of a base, preferably sodium tert-butoxide, in an organic        solvent, preferably toluene, at a range of temperature of 80° to        120° C.    -   b) The hydrolysis of the resulting compound (XI_(ex)) in an        acidic medium, preferably HCl in an organic solvent, preferably        1,4-dioxane.

Method IIIB comprises the reaction of compounds of formula (IX_(ex))with a compound of formula (Xb_(ex)) at a range of temperature of 80 to220° C. in a polar solvent, preferably n-buthanol. Alternatively, thereaction can be carried out with microwave irradiation.

Method IV

Intermediates of general formula (IIb_(ex)) may be prepared according tothe reaction sequence shown in scheme 4 (Method IV).

-   -   a) Method IVA comprises the reductive amination reaction of the        intermediate (XIa_(ex)) with an aldehyde of general formula        (XII_(ex)) in the presence of a reductive reagent, preferably        sodium triacetoxyborohydride, in an aprotic solvent, preferably        dichloroethane; in some cases, in the presence of an acid as        additive, preferably acetic acid.    -   Method IVB comprises the reaction of the intermediate (XIa_(ex))        with a compound of general formula (XIII_(ex)) where X is a        suitable leaving group such as an halogen or sulfonate, in the        presence of a base, in an organic solvent.    -   b) The hydrolysis of the resulting compound (XIb_(ex)) in an        acidic medium, preferably HCl in an organic solvent, preferably        1,4-dioxane.

Method V

The process for the preparation of intermediates of general formula(IIc_(ex)-e_(ex)) where W, R₂ R₇, R₈, and R₉ have the meanings asdefined above (with “W” being “V¹” in the above description), accordingto the reaction sequence shown in scheme 5, which comprises:

-   -   a) The reaction of intermediate (XIV_(ex)) with a compound of        formula (XVa_(ex)-c_(ex), where X is a suitable leaving group,        such as halogen, in the presence of a base, preferably pyridine,        Et₃N, NaH, K₂CO₃ or Cs₂CO₃ at a range of temperature of 0° C. to        120° C., in the presence of a suitable solvent, such as        dichloromethane or alternatively, the reactions can be carried        out in a microwave reactor.    -   b) The deprotection of the resulting compounds        (XVIa_(ex)-c_(ex)) in an acidic medium, preferably HCl in an        organic solvent, preferably 1,4-dioxane.

Synthesis of Intermediates of General Formula III

The aldehydes of general formula (III_(ex)) where R₃, R₄, A, B, Y, Z andn have the meanings as defined above (with “A”, “B”, “Y”, and “Z” being“X”, “Y”, “W”, “Z” in the above description, respectively), arecommercially available or can be prepared by methods described in thebibliography (for example, WO2010046780 A2, WO2008157844 A1) or by themethods described below and summarized in Scheme 6.

Method VI involves the oxidation of compounds of general formula(XVII_(ex)), using a suitable oxidizing reagent, such as MnO₂, in anaprotic solvent such as dichloromethane.

Method VII involves the reduction of compounds of general formula(XVIII_(ex)) with a suitable reducing agent such as DIBAL-H at −78° C.in an aprotic solvent, preferably dichloromethane.

Method VIII, which is exemplified for the preparation of compounds offormula IIIa, comprises the reaction between compounds of formula(XIX_(ex)) with compounds of general formula (VII_(ex)) where X is asuitable leaving group as an halogen or sulfonate, in the presence of aninorganic base, preferably K₂CO₃, in a polar solvent preferably DMF at140° C. using microwaves irradiation. Alternatively, using an aqueoussolution of NaOH as base and a phase transfer catalyst, preferablytetra-n-butylammonium bromide, in an aprotic solvent, preferably tolueneat room temperature. Alternatively, using proline and CuI as catalysts,in the presence of a base, preferably K₂CO₃, in a polar solvent,preferably DMSO at a temperature range of 90-110° C.

Method IX, which is exemplified for the preparation of compounds offormula IIIb, comprises the reaction between the compounds of generalformula (XX_(ex)) with POCl₃ in DMF as solvent at 90-110° C.

Synthesis of Intermediates of General Formula XVII

The alcohols of general formula (XVII_(ex)) where R₃, R₄, A, B, Y, Z andn have the meanings as defined above (with “A”, “B”, “Y”, and “Z” being“X”, “Y”, “W”, “Z” in the above description, respectively), arecommercially available or can be prepared by methods described in thebibliography (for example J. Org. Chem. 2010, 75, 6540-6548,WO2010080864, Org. Lett. 2009, 21, 4954-4957, J. Med. Chem. 2011, 54,5988-5999). In particular, alcohols of formula XVIIa_(ex) and XVIIb_(ex)can be prepared by the methods outlined in Scheme 7.

Method X comprises the cycloaddition reaction of an azide of generalformula (VI_(ex)) with propargyl alcohol in the presence of a coppersalt as catalyst. The azides of general formula (VI_(ex)) arecommercially available or may be prepared following conventional methodsreported in the literature; alternately, some of the azides can beprepared in situ. The reaction is performed in the presence of a coppersalt, preferably CuSO₄.5H₂O and sodium ascorbate in a mixture of proticorganic solvent and water, preferably a mixture of t-BuOH:H₂O 1:1 atroom temperature Alternatively, CuI can be used as copper salt in apolar solvent as dimethylformamide at 100° C. using microwaveirradiation or Cu(OAc)₂ can be used as copper salt in a polar solvent,such as tert-butanol at room temperature. The reaction can also beeffected using a one-pot procedure, in which case it is performed latewith sodium azide in a mixture of protic organic solvent and water,preferably a mixture of t-BuOH:H₂O 1:1, heating at 100° C. usingmicrowave irradiation for 1 h or until completed reaction, followed bythe reaction with propargyl alcohol in the presence of a copper salt,preferably CuSO₄.5H₂O and sodium ascorbate at room temperature.

Compounds of general formula (XVIIb_(ex)), where R₃, R₄, and n have themeanings as defined above can be prepared using Method XI. This processcomprises:

-   -   a) The reaction between compound of formula (XXI_(ex)) with a        compound of general formula (VII_(ex)) where X is a suitable        leaving group such as an halogen or sulfonate, in the presence        of a base, preferably K₂CO₃, in a polar solvent, preferably        acetone at 60° C.    -   b) The reduction of the resulting compound (XVIIIb_(ex)) with a        suitable hydride reagent, preferably LiAIH₄ at 0° C., in an        aprotic solvent, preferably THF.

Synthesis of Intermediates of General Formula XVIII

The esters of general formula (XVIII_(ex)), where R₃, R₄, A, B, Y, Z andn have the meanings as defined above (with “A”, “B”, “Y”, and “Z” being“X”, “Y”, “W”, “Z” in the above description, respectively), arecommercially available or can be prepared by methods described in thebibliography (Synthesis, 1975, 9, 609-610; WO2011098904; Org. Lett.2010, 12, 9, 2166-2169, Org. Lett. 2008, 10, 5389-5392). In particular,esters of general formula XVIIIa_(ex) and XVIIIb_(ex) can be prepared bythe methods outlined in Scheme 8.

Method XII comprises the cycloaddition reaction of an azide of generalformula (VI_(ex)) with ethyl propiolate in the presence of a copper saltas catalyst, preferably Cu(OTf)₂*C₆H₆ in an aprotic solvent, preferablytoluene, at 70-100° C.

Method XIII comprises the reaction between compound of formula(XXII_(ex)) with a compound of general formula (VII_(ex)) where X is asuitable leaving group such as an halogen or sulfonate, in the presenceof a base, preferably K₂CO₃, a copper salt, preferably CuCl, and aligand, preferably proline, in a polar solvent, preferably DMSO at85-170° C. under microwaves irradiation.

Synthesis of Intermediates Examples of Preparation of an Intermediate ofFormula (V_(ex)), Method IIA Synthesis ofN-(6-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide

A suspension of N-(6-piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide(85 mg, 0.30 mmol), Et₃N (54 μl, 0.39 mmol) and propargyl bromide (37μL, 80% wt in toluene, 0.33 mmol) in THF (4.5 ml) was irradiated withmicrowaves at 75° C. for 1 h. The reaction mixture was cooled and thesolvent evaporated. Purification by flash chromatography, silica gel,gradient hexane to ethyl acetate afforded the title product (54 mg, 56%yield). ¹H-NMR (300 MHz, CDCl₃), δ ppm: 7.41 (t, J=8 Hz, 1H), 7.14 (bs,1H), 6.49 (d, J=8 Hz, 1H), 6.32 (d, J=8 Hz, 1H), 3.57 (septet, J=7 Hz,1H), 3.54 (m, 4H), 3.35 (d, J=2.4 Hz, 2H), 2.64 (m, 4H), 2.27 (t, J=2.4Hz, 1H), 1.41 (d, J=7 Hz, 6H).

Example of Preparation of an Intermediate of Formula (IIa_(ex)), MethodIIIa Synthesis of N-(3-(pyrrolidin-3-ylamino)phenyl)methanesulfonamide

tert-Butyl3-((3-methylsulfonamido)phenyl)amino)pyrrolidine-1-carboxylate

An oven-dried schlenk was evacuated and backfilled with argon. The flaskwas charged with Pd(OAc)₂ (5 mg, 0.022 mmol),[1,1′-biphenyl]-2-yldi-tert-butylphosphine (13 mg, 0.045 mmol), NaOtBu(38 mg, 0.392 mmol), and N-(3-bromophenyl) methanesulfonamide (70 mg,0.280 mmol) and evacuated and backfilled with argon. Toluene (0.6 mL)and tert-butyl 3-aminopyrrolidine-1-carboxylate (61 μl; 0.336 mmol) wereadded and heated at 100° C. for 2 h. The reaction mixture was cooled andfiltered through a pad of celite and the solvent was removed. The crudewas purified by flash chromatography, silica gel, gradient from hexaneto hexane:ethyl acetate (1:1) to afford the desired product (55 mg, 55%yield). ¹H-NMR (500 MHz, CDCl₃), δ ppm: 7.15 (m, 1H), 6.94 (bs, 1H),6.56 (m, 2H), 6.42 (d, J=7.3 Hz, 1H), 4.03 (m, 2H), 3.74 (m, 1H), 3.51(m, 2H), 3.28 (m, 1H), 3.02 (s, 3H), 2.20 (m, 1H), 1.90 (m, 1H), 1.49(s, 9H).

N-(3-(Pyrrolidin-3-ylamino)phenyl)methanesulfonamide

To a solution of tert-butyl3-((3-(methylsulfonamido)phenyl)amino)pyrrolidine-1-carboxylate (80 mg,0.225 mmol) in dioxane (0.40 ml) was added a solution of 4M HCl indioxane (0.78 ml, 3.15 mmol) and stirred at rt overnight. The reactionmixture was concentrated to afford the desired product as ahydrochloride (74 mg, 100%). ¹H-NMR (400 MHz, CD₃OD), δ ppm: 7.35 (m,1H), 7.00 (m, 1H), 6.87 (m, 1H), 6.73 (m, 1H), 4.40 (m, 1H), 3.70 (m,2H), 3.56 (m, 2H), 3.11 (s, 3H), 2.50 (m, 1H), 2.30 (m, 1H).

Example of Preparation of an Intermediate of Formula (IIa_(ex)), MethodIIIb Synthesis ofN-(6-(piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide

N-(6-Bromopyridin-2-yl)cyclopropanesulfonamide

To a solution of 6-bromopyridin-2-amine (300 mg, 1.73 mmol) in pyridine(2 ml), cyclopropanesulfonyl chloride (317 mg, 2.25 mmol) was added andthe mixture was heated at 50° C. in a sealed tube for 16 h. The reactionmixture was concentrated and purified by flash chromatography, silicagel, gradient from hexane to hexane:ethyl acetate (1:1) to afford thedesired product (400 mg, 83% yield). ¹H-NMR (400 MHz, CDCl₃), 5 ppm:7.55 (t, J=8 Hz, 1H), 7.40 (bs, 1H), 7.34 (dd, J=8, 1 Hz, 1H), 7.25 (dd,J=8, 1 Hz, 1H), 2.72 (m, 1H), 1.31 (m, 1H), 1.07 (m, 1H).

N-(6-(Piperazin-1-yl)pyridin-2-yl)cyclopropanesulfonamide

In a sealed tube, a mixture ofN-(6-bromopyridin-2-yl)cyclopropanesulfonamide (100 mg, 0.36 mmol) andpiperazine (311 mg, 3.61 mmol) in n-BuOH (4.5 ml) was irradiated with MWat 200° C. for 1 h. The reaction mixture was concentrated and purifiedby flash chromatography, silica gel, gradient from dichloromethane to35% MeOH to afford the desired product (96 mg, 94% yield) as whitesolid. ¹H-NMR (300 MHz, CD₃OD), δ ppm: 7.52 (t, J=8 Hz, 1H), 6.51 (d,J=8 Hz, 1H), 6.41 (d, J=8 Hz, 1H), 3.74 (m, 4H), 3.19 (m, 4H), 3.01 (m,1H), 1.18 (m, 2H), 1.03 (m, 1H).

Example of Preparation of an Intermediate of Formula (IIb_(ex)), MethodIVA Synthesis ofN-(3-(methyl(pyrrolidin-3-yl)amino)phenyl)methanesulfonamide

tert-Butyl3-(methyl(3-(methylsulfonamido)phenyl)amino)pyrrolidine-1-carboxylate

To a solution of tert-butyl3-((3-(methylsulfonamido)phenyl)-amino)pyrrolidine-1-carboxylate (55 mg,0.15 mmol) in dichloroethane (3 mL), paraformaldehyde (20 mg, 0.61mmol), NaBH(OAc)₃ (131 mg, 0.61 mmol) and acetic acid (8.9 μL, 0.15mmol) were added. The reaction mixture was stirred at r.t. overnight ina sealed tube. An aqueous NaHCO₃ saturated solution was added andextracted with dichloromethane. The organic phases were dried overNa₂SO₄ and the solvent was removed to afford the title product (54 mg,94%). ¹H-NMR (400 MHz, CDCl₃), δ ppm: 7.20 (dd, J=7.8, 8.4 Hz, 1H), 6.79(bs, 1H), 6.71 (t, J=2.2 Hz, 1H), 6.65 (dd, J=2.2, 8.4 Hz, 1H), 6.61 (d,J=7.8 Hz, 1H), 4.40 (m, 1H), 3.56 (m, 2H), 3.36 (m, 2H), 3.02 (s, 3H),2.85 (s, 3H), 2.10 (m, 2H), 1.49 (s, 9H).

N-(3-(Methyl(pyrrolidin-3-yl)amino)phenyl)methanesulfonamide

To a solution of tert-butyl3-(methyl(3-(methylsulfonamido)phenyl)amino)pyrrolidine-1-carboxylate(54 mg, 0.14 mmol) in dioxane (0.27 ml), a solution of 4M HCl in dioxane(0.51 ml; 2.04 mmol) was added. The reaction mixture was stirred at rtovernight. The mixture was concentrated to afford the title product as ahydrochloride (50 mg, 100%). ¹H-NMR (500 MHz, CD₃OD), δ ppm: 7.68 (bs,1H), 7.55 (m, 2H), 7.36 (d, J=7.5 Hz, 1H), 4.80 (m, 1H), 3.70 (m, 3H),3.45 (m, 1H), 3.34 (s, 3H), 3.10 (s, 3H), 2.43 (m, 2H).

Example of Preparation of an Intermediate of Formula (IIc_(ex)), MethodV Synthesis of N-(3-(piperazin-1-yl)phenyl)propane-2-sulfonamide

tert-Butyl4-(3-(1-methylethylsulfonamido)phenyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate(100 mg, 0.36 mmol) in pyridine (0.44 ml, 5.41 mmol), isopropylsulfonylchloride (48 μl, 0.43 mmol) was added and the reaction mixture wasstirred at 50° C. overnight. Solvent was removed under vacuum and theresidue was purified by flash chromatography, silica gel, gradient fromhexane to ethyl acetate to afford the desired product (87 mg, 63%yield). ¹H-NMR (400 MHz, CDCl₃), δ ppm: 7.20 (t, J=8 Hz, 1H), 6.87 (s,1H), 6.71 (m, 2H), 6.56 (s, 1H), 3.59 (m, 4H), 3.33 (septet, J=7 Hz,1H), 3.16 (m, 4H), 1.50 (s, 9H), 1.40 (d, J=7 Hz, 6H).

N-(3-(Piperazin-1-yl)phenyl)propane-2-sulfonamide

To a solution of tert-butyl4-(3-(1-methylethylsulfonamido)phenyl)piperazine-1-carboxylate (64 mg,0.17 mmol) in dioxane (0.3 ml), a solution of 4M HCl in dioxane (0.6 ml,2.34 mmol) was added and stirred at rt overnight. The mixture wasconcentrated to dryness to afford the title compound (57 mg, 96% yield)as hydrochloride. ¹H-NMR (300 MHz, MeOD) δ ppm: 7.27 (t, J=8 Hz, 1H),7.00 (s, 1H), 6.84 (m, 2H), 3.44 (m, 8H), 3.32 (septet, J=7 Hz, 1H),1.36 (d, J=7 Hz, 6H).

Examples of Preparation of an Intermediate of Formula (III_(ex)), MethodVI Synthesis of 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carbaldehyde

To a solution of (1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanol (100mg, 0.52 mmol) in dry dichloromethane (5 ml), MnO₂ (465 mg, 4.70 mmol)was added and the resulting dark solution was stirred during 4 h at rt.Then, the reaction mixture was filtered on Celite and the solvent wasremoved under vacuum to afford the desired product (84 mg, 74% yield).¹H-NMR (400 MHz, CDCl₃), δ ppm: 10.24 (s, 1H), 8.64 (d, J=2 Hz, 1H),8.00 (td, J=8, 1 Hz, 1H), 7.52 (m, 1H), 7.32-7.41 (m, 2H).

Examples of Preparation of an Intermediate of Formula (III_(ex)), MethodVII Synthesis of1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazole-4-carbaldehyde

DIBAL-H (0.95 ml, 1 M in DCM, 0.95 mmol) was added dropwise to asolution of ethyl1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazole-4-carboxylate (204 mg, 0.86mmol) in dichloromethane (9 mL) at −78° C. under argon atmosphere. Theresulting mixture was stirred for 1 h at this temperature and then anadditional amount of DIBAL-H (0.95 ml, 1 M in DCM, 0.95 mmol) was added.After stirring for 1 h at −78° C., the mixture was quenched withmethanol and water at −78° C. Then, the reaction mixture was filtered oncelite and the filtrate was washed with dichloromethane. The solvent wasremoved under vacuum and the residue was purified by flashchromatography, silica gel, gradient hexane to ethyl acetate to providethe desired product (146 mg, 88% yield) as a white solid. ¹H-NMR (500MHz, CDCl₃), δ ppm: 10.24 (s, 1H), 9.04 (s, 1H), 8.40 (d, J=3 Hz, 1H),8.28 (dd, J=9, 4 Hz, 1H), 7.71 (ddd, J=9, 7, 3 Hz, 1H) Examples ofpreparation of an intermediate of formula (IIIa_(ex)), Method VIII

Synthesis of 1-(pyridin-2-yl)-1H-imidazole-4-carbaldehyde

A mixture of K₂CO₃ (283 mg, 2.05 mmol), 2-bromopyridine (162 mg, 1.02mmol) and 1H-imidazole-4-carbaldehyde (108 mg, 1.128 mmol) in DMF (5 ml)was irradiated with microwaves at 140° C. for 1.5 h. Water was added andthe aqueous phase was extracted with dichloromethane. The combinedorganic phases were washed with brine and water, dried over Na₂SO₄,filtered and concentrated. Purification by flash chromatography, silicagel, gradient from dichloromethane to 30% methanol afforded the titleproduct (12 mg, 6% yield). ¹H-NMR (500 MHz, CDCl₃), δ ppm: 9.99 (s, 1H),8.56 (m, 1H), 8.46 (d, J=1.3 Hz, 1H), 8.35 (d, J=1.3 Hz, 1H), 7.92 (m,1H), 7.46 (m, 1H), 7.37 (m, 1H).

Synthesis of 1-(2-fluorophenyl)-1H-imidazole-4-carbaldehyde

To a mixture of S-Proline (48 mg, 0.416 mmol) and CuI (79 mg, 0.416mmol) under argon atmosphere, anh. DMSO (4 mL) was added and the mixturewas stirred for 5 min at rt. Imidazole-4-carbaldehyde (200 mg, 2.08mmol), 1-fluoro-2-iodobenzene (508 mg, 2.29 mmol) and anh. K₂CO₃ (863mg, 6.24 mmol) were added and the mixture was heated at 90° C. for 16 h.The reaction mixture was cooled at rt, DCM was added and washed withNH₄Cl sat. solution and brine, dried over Na₂SO₄, filtered andconcentrated. Purification by flash chromatography, silica gel, gradientfrom hexane to hexane:ethyl acetate (1:1) afforded the title product (73mg, 18% yield). ¹H-NMR (500 MHz, CDCl₃), b ppm: 9.97 (s, 1H), 7.93 (m,1H), 7.88 (m, 1H), 7.43 (m, 2H), 7.31 (m, 2H).

Examples of Preparation of an Intermediate of Formula (IIIb_(ex)),Method IX Synthesis of 1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

To a solution of 2-(1H-pyrazol-1-yl)pyridine (128 mg, 0.88 mmol) in DMF(0.7 ml) at 0° C., POCl₃ (0.68 ml, 7.50 mmol) was added. The mixture wasstirred at this temperature for 10 min and then heated at 95° C. for 3h. Purification by flash chromatography, silica gel, gradient fromhexane to ethyl acetate afforded the desired product (40 mg, 31% yield)as a yellow oil. ¹H-NMR (400 MHz, CDCl₃), δ ppm: 10.00, (s, 1H), 9.10(d, J=1 Hz, 1H), 8.46 (ddd, J=5, 2, 1 Hz, 1H), 8.17 (s, 1H), 8.03 (dt,J=8, 1 Hz, 1H), 7.22 (ddd, J=8, 8, 5 Hz, 1H), 7.30 (ddd, J=8, 5, 1 Hz,1H).

Examples of Preparation of an Intermediate of Formula (XVIIa_(ex)),Method XA Synthesis of(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanol

Propargyl alcohol (64 mg, 1.12 mmol) was added to a mixture of1-azido-2-fluorobenzene (143 mg, 0.94 mmol), CuSO₄.5H₂O (29 mg, 0.12mmol) and sodium ascorbate (40 mg, 0.2 mmol) in t-BuOH:H₂O 1:1 (10 mL)and the reaction mixture was stirred at rt overnight. An aqueous NH₄Clsaturated solution was added and the mixture was extracted with EtOAc;the organic phase was washed with NH₄Cl saturated solution, brine, driedover Na₂SO₄, filtered and concentrated. Purification by flashchromatography, silica gel, gradient dichloromethane to 10% methanolafforded the title product (101 mg, 56% yield). ¹H-NMR (500 MHz, CDCl₃),δ ppm: 8.08 (d, J=2 Hz, 1H), 7.93 (td, J=8, 1 Hz, 1H), 7.43 (m, 1H),7.26-7.35 (m, 2H), 4.90 (s, 2H), 2.94 (bs, 1H).

Example of Preparation of an Intermediate of Formula (XVIIb_(ex)),Method XI Synthesis of 1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)methanol

Ethyl 1-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl-1H-pyrazole-4-carboxylate (450 mg, 3.15 mmol) inacetone (6.3 mL) K₂CO₃ (976 mg, 7.06 mmol), 2-(chloromethyl)pyridinehydrochloride (516 mg, 3.15 mmol) and TBAI (119 mg, 0.32 mmol) wasadded. The mixture was heated at 60° C. overnight. The reaction mixturewas cooled and filtered to remove any solids. The filtrate wasconcentrated. Purification by flash chromatography, silica gel, gradienthexane to ethyl acetate afforded the desired product (605 mg, 83% yield)as a yellow oil. ¹H-NMR (300 MHz, CDCl₃), δ ppm: 8.57 (d, J=5 Hz, 1H),8.03 (s, 1H), 7.94 (s, 1H), 7.65 (td, J=8, 2 Hz, 1H), 7.22 (dd, J=8, 5Hz, 1H), 7.11 (d, J=8 Hz, 1H), 5.45 (s, 2H), 4.30 (q, J=7 Hz, 2H), 1.34(t, J=7 Hz, 3H).

1-(Pyridin-2-ylmethyl)-1H-pyrazol-4-yl)methanol

To a solution of ethyl 1-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate(597 mg, 2.58 mmol) in THF (5 ml) cooled at 0° C. under inertatmosphere, LiAIH₄ (1M in THF, 2.58 mL, 2.58 mmol) was added dropwise.The solution was allowed to warm at rt and stirred for 2 h. An aqueousNH₄Cl saturated solution was slowly added and the solvent was removed.Water and ethyl acetate were added, the organic phase was decanted,dried over Na₂SO₄ and filtered. The solvent was removed to afford thetitle product (320 mg, 65% yield). ¹H-NMR (300 MHz, CDCl₃), b ppm: 8.55(d, J=4.7 Hz, 1H), 7.64 (td, J=7.8, 2 Hz, 1H), 7.54 (d, J=4.7 Hz, 2H),7.21 (dd, J=7.4, 4.7 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 5.40 (s, 2H), 4.59(s, 2H).

Example of Preparation of an Intermediate of Formula (XVIIIa_(ex)),Method XII Synthesis of ethyl1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazole-4-carboxylate

2-Azido-5-fluoropyridine

A microwave vial was charged with a solution of 2-bromo-5-fluoropyridine(0.52 g, 2.96 mmol), NaN₃ (196 mg, 3.01 mmol), sodium ascorbate (31 mg,0.15 mmol), CuI (57 mg, 0.30 mmol), N,N′-dimethylethylenediamine (49 μL,0.44 mmol) and a mixture of EtOH:H₂O (7:3) (12.4 mL) and the mixture wasirradiated with microwaves at 100° C. for 60 min. The reaction mixturewas cooled, water was added and extracted with ethyl acetate. Theorganic phase was dried over Na₂SO₄ and the solvent was removed toafford the title product (0.27 g, 66% yield) as a yellow solid. ¹H-NMR(400 MHz, CDCl₃), δ ppm: 8.77 (td, J=3, 1 Hz, 1H), 8.06 (dd, J=12, 6 Hz,1H), 7.62 (ddd, J=12, 9, 3 Hz, 1H).

Ethyl 1-(5-fluoropyridin-2-yl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of 2-azido-5-fluoropyridine (0.32 g, 1.97 mmol) and(CuOTf)₂.C₆H₆ (112 mg, 0.20 mmol) under argon, dry toluene (7.7 mL) wasadded, followed by ethyl propiolate (240 μL, 2.36 mmol). The reactionmixture was stirred at 100° C. overnight. Toluene was removed underreduced pressure and the reaction mixture was then diluted withdichloromethane, washed with water, brine and dried over Na₂SO₄. Themixture was filtered and the filtrate was concentrated under reducedpressure. Purification by flash chromatography, silica gel, gradienthexane to ethyl acetate afforded the desired product (450 mg, 97%yield). ¹H-NMR (500 MHz, CDCl₃), δ ppm: 9.00 (s, 1H), 8.38 (d, J=3 Hz,1H), 8.27 (dd, J=9, 4 Hz, 1H), 7.68 (ddd, J=9, 7, 3 Hz, 1H), 4.47 (q,J=7 Hz, 2H), 1.44 (t, J=7 Hz, 3H).

Example of Preparation of an Intermediate of Formula (XVIIIb_(ex)),Method XIII Synthesis of ethyl2-(pyridine-2-yl)-2H-1,2,3-triazole-4-carboxylate

A microwave vial was charged with ethyl 2H-1,2,3-triazole-4-carboxylate(250 mg, 1.50 mmol), K₂CO₃ (416 mg, 3.01 mmol), L-proline (35 mg, 0.30mmol) and CuCl (15 mg, 0.15 mmol). The mixture was evacuated andbackfilled with argon, DMSO (1.25 mL) and 2-bromopyridine (357 mg, 2.25mmol) were added and the mixture was irradiated with microwaves at 160°C. for 40 min. After cooling, water was added and extracted with ethylacetate. The combined organic phases were washed with brine and driedover Na₂SO₄. The solvent was removed under vacuum. Purification by flashchromatography, silica gel, gradient from hexane to ethyl acetateafforded the title product (40 mg, 12% yield). ¹H-NMR (300 MHz, CDCl₃),δ ppm: 8.65 (m, 1H), 8.32 (s, 1H), 8.17 (m, 1H), 7.94 (m, 1H), 7.41 (m,1H), 4.48 (q, J=7 Hz, 2H), 1.44 (t, J=7 Hz, 3H).

Synthesis of Examples Example of Preparation of Compounds of GeneralFormula (I_(ex)), Method I Example 1:N-(3-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenyl)-propane-2-sulfonamide

To a suspension of N-(3-(piperazin-1-yl)phenyl)propane-2-sulfonamidehydrochloride (1.06 g, 2.99 mmol) in dichloroethane (60 mL),N,N-diisopropylethylamine (2.09 mL, 11.98 mmol) was added and themixture was stirred at rt for 5 min. Then,1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (0.67 g, 3.91 mmol) andNaBH(OAc)₃ (1.34 g, 6.03 mmol) were added and the reaction mixture wasstirred at rt overnight. Dichloromethane was added and washed withNaHCO₃ sat solution and brine, dried over Na₂SO₄, filtered andconcentrated. Purification by flash chromatography, silica gel, gradientfrom hexane to ethyl acetate afforded the title product (1.22 g, 93%yield). HPLC retention time: 5.61 min; HRMS: 441.2068 (M+H).

This method was used for the preparation of the examples of formula(I_(ex)) 1, 3-45, 47-49, 51-55, 57-73.

Example of Preparation of Compounds of General Formula (Ia_(ex)), MethodIIB Example 2:N-(6-(4-((1-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide

A mixture ofN-(6-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyridin-2-yl)propane-2-sulfonamide(55 mg, 0.17 mmol), 3-azido-5-chloropyridine (40 mg, 0.25 mmol),CuSO₄.5H₂O (4.3 mg, 0.017 mmol) and sodium ascorbate (6.7 mg, 0.034mmol) in t-BuOH:H₂O 1:1 (6 ml) was stirred at rt for 3 days. Ethylacetate was added to the reaction mixture and washed with saturatedNH₄Cl aqueous solution and brine, dried over Na₂SO₄ and concentrated.Purification was carried out by flash chromatography, silica gel,gradient hexane to acetone to afford the title product (66 mg, 81%yield). HPLC retention time: 5.27 min; HRMS: 475.1433 (M−H).

This method was used for the preparation of the examples of formula(Ia_(ex)) 2, 46, 50, 56.

Table of Examples with Results of HRMS and Binding to the μ-OpioidReceptor and the σ1-Receptor:

HPLC:

column: Agilent Eclipse XDB-C18, 4.6×150 mm, 5 mm, flux: 1 ml/min.

A:H₂O (0.05% TFA), B:ACN.

Conditions: 1°/gradient 5% to 95% B in 7 min. 2°/isocratic 95% B 5 min.

HRMS:

Source type: ESI; Ion Polarity: Positive or Negative

Ret time EX Structure Chemical name (min) HRMS 1

N-(3-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenyl)propane-2- sulfonamide 5.61 441.2068 (M + H) 2

N-(6-(4-((1-(5- chloropyridin-3-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.27475.1433 (M − H) 3

N-(3-(4-((1-benzyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenyl) methanesulfonamide 5.26 425.1758 (M − H) 4

N-(3-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenyl) methanesulfonamide 5.22 413.1766 (M + H) 5

3-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1- yl)phenol5.12 334.1672 (M − H) 6

3-(4-((1-benzyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1- yl)phenol5.11 348.1828 (M − H) 7

3-(4-((1-(pyridin-2-yl)- 1H-1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenol 4.73 335.1620 (M − H) 8

N-(3-(4-((1-(6- (trifluoromethyl)pyridin- 3-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1- yl)phenyl) methanesulfonamide 5.49 482.1585 (M +H) 9

N-(3-(4-((1-(2- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 5.59 459.1973(M + H) 10

N-(3-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenyl) ethanesulfonamide 5.38 427.1913 (M + H) 11

N-(3-(1-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)pyrrolidin-3-ylamino)phenyl) methanesulfonamide 5.21 411.1601 (M − H) 12

N-(3-(1-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)azetidin-3-ylamino)phenyl) methanesulfonamide 5.19 399.1609 (M + H) 13

N-(3-(5-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl) hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)phenyl) methanesulfonamide 5.43 439.1918 (M + H)14

N-(3-(methyl(1-((1- phenyl-1H-1,2,3-triazol- 4-yl)methyl)pyrrolidin-3-yl)amino)phenyl) methanesulfonamide 5.40 427.1917 (M + H) 15

N-(3-(methyl(1-((1- phenyl-1H-1,2,3-triazol- 4-yl)methyl)azetidin-3-yl)amino)phenyl) methanesulfonamide 5.35 413.1763 (M + H) 16

N-(3-(4-((1-(pyridin-2- ylmethyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 4.86 456.2187(M + H) 17

N-(3-(4-((1-(pyridin-2-yl)- 1H-1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenyl)propane-2- sulfonamide 5.26 442.2032 (M + H) 18

1,1,1-trifluoro-N-(3-(4- ((1-phenyl-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)phenyl) methanesulfonamide 6.14 467.1   (M +H) 19

N-(3-(4-((1-(5- fluoropyridin-2-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 5.49 460.1928(M + H) 20

N-(3-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenyl) cyclopropanesulfonamide 5.14 437.1   (M − H) 21

N-(3-(4-((1-(3- fluoropyridin-2-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 5.17 460.1936(M + H) 22

N-(3-(4-((1-(4- fluoropyridin-2-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 5.49 460.1934(M + H) 23

N-(3-((1R,5S)-3-((1- phenyl-1H-1,2,3-triazol- 4-yl)methyl)-3,8-diazabicyclo[3.2.1] octan-8- yl)phenyl) methanesulfonamide 5.30 439.1912(M + H) 24

N-(3-(4-((2-(pyridin-2-yl)- 2H-1,2,3-triazol-4- yl)methyl)piperazin-1-yl)phenyl)propane-2- sulfonamide 5.18 442.2028 (M + H) 25

N-(3-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)-1,4-diazepan-1-yl)phenyl) methanesulfonamide 5.35 427.2   (M + H) 26

N-(3-(methyl(1-((1- phenyl-1H-1,2,3-triazol- 4-yl)methyl)pyrrolidin-3-yl)amino)phenyl)propane- 2-sulfonamide 5.81 455.2236 (M + H) 27

N-(3-(4-((1-(3- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 5.78 459.1980(M + H) 28

N-(3-(4-((1-(4- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 5.74 459.1981(M + H) 29

N-(3-(4-((1-(6- fluoropyridin-2-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)phenyl)propane-2- sulfonamide 5.56 458.1781 (M− H) 30

N-(3-(5-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)phenyl)propane-2- sulfonamide 5.88 465.2   (M −H) 31

3-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1- yl)aniline4.45 335.1983 (M + H) 32

N-tert-butyl-3-(4-((1- phenyl-1H-1,2,3-triazol- 4-yl)methyl)piperazin-1-yl)benzenesulfonamide 5.01 455.2227 (M + H) 33

N-(3-(4-((1-phenyl-1H- pyrazol-4- yl)methyl)piperazin-1- yl)phenyl)methanesulfonamide 4.88 410.1666 (M − H) 34

N-(3-(4-((1-benzyl-1H- pyrazol-4- yl)methyl)piperazin-1- yl)phenyl)methanesulfonamide 5.29 424.1813 (M − H) 35

N-(3-(4-((1-(pyridin-2- ylmethyl)-1H-pyrazol-4- yl)methyl)piperazin-1-yl)phenyl) methanesulfonamide 4.27 425.1767 (M − H) 36

N-(3-(4-((1-phenyl-1H- pyrazol-4- yl)methyl)piperazin-1-yl)phenyl)propane-2- sulfonamide 5.69 438.1963 (M − H) 37

3-(4-((1-phenyl-1H- pyrazol-4- yl)methyl)piperazin-1- yl)phenol 5.26333.1720 (M − H) 38

N-(3-(4-((1-(pyridin-2-yl)- 1H-pyrazol-4- yl)methyl)piperazin-1-yl)phenyl) methanesulfonamide 5.04 413.1755 (M + H) 39

N-(3-(4-((1-(pyridin-2-yl)- 1H-pyrazol-4- yl)methyl)piperazin-1-yl)phenyl)propane-2- sulfonamide 5.12 441.2083 (M + H) 40

N-(3-(4-((1-benzyl-1H- imidazol-4- yl)methyl)piperazin-1-yl)phenyl)propane-2- sulfonamide 5.09 452.2120 (M − H) 41

N-(6-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl) methanesulfonamide 5.10 414.1721 (M + H) 42

N-(6-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl)propane- 2-sulfonamide 5.47 442.2022 (M + H) 43

N-(6-(4-((1-(2- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.54460.1922 (M + H) 44

N-(6-(4-((1-(2- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl) cyclopropanesulfonamide 5.47458.1768 (M + H) 45

N-(6-(4-((1-(2- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)pyridin-2- yl)propionamide 5.30 410.2092 (M +H) 46

N-(6-(4-((1-(2- hydroxyphenyl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.23456.1819 (M − H) 47

N-(6-(4-((1-(pyridin-2-yl)- 1H-pyrazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl)propane- 2-sulfonamide 5.27 442.1   (M + H) 48

N-(6-(4-((1-(2,6- difluorophenyl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.48478.1   (M + H) 49

N-(6-(4-((1-(3,4- difluorophenyl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.70478.1   (M + H) 50

N-(6-(4-((1-(4-chloro-2- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.82494.1549 (M + H) 51

N-(6-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl) cyclopropanesulfonamide 5.35 440.1861 (M + H) 52

N-(5-chloro-6-(4-((1- phenyl-1H-1,2,3-triazol- 4-yl)methyl)piperazin-1-yl)pyridin-2-yl)propane- 2-sulfonamide 5.69 476.1636 (M + H) 53

N-(6-(5-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl) hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyridin-2-yl)propane- 2-sulfonamide 5.55468.2179 (M + H) 54

N-(6-(5-((1-benzyl-1H- 1,2,3-triazol-4- yl)methyl) hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyridin-2-yl)propane- 2-sulfonamide 5.51482.2335 (M + H) 55

N-(6-(5-((1-(pyridin-2- ylmethyl)-1H-1,2,3- triazol-4- yl)methyl)hexahydropyrrolo [3,4-c]pyrrol-2(1H)- yl)pyridin-2-yl)propane-2-sulfonamide 4.84 483.2284 (M + H) 56

N-(6-(4-((1-(5- methoxypyridin-3-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.01473.2068 (M + H) 57

N-(6-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)-1,4-diazepan-1-yl)pyridin-2- yl)propane-2- sulfonamide 5.54 456.2182 (M + H) 58

N-(6-(4-((1-(5- chloropyridin-2-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl)propane- 2-sulfonamide 5.59477.1580 (M + H) 59

N-(6-(4-((1-(pyridin-2- ylmethyl)-1H-1,2,3- triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2- yl)propane-2- sulfonamide 4.80 493.2111 (M +Na) 60

N-(6-(4-((1-(2- fluorophenyl)-1H-1,2,3- triazol-4-yl)methyl)-1,4-diazepan-1-yl)pyridin-2- yl)propane-2- sulfonamide 5.57 474.2094 (M + H)61

N-(6-(5-((1-(2- fluorophenyl)-1H-1,2,3- triazol-4- yl)methyl)hexahydropyrrolo [3,4-c]pyrrol-2(1H)- yl)pyridin-2-yl)propane-2-sulfonamide 5.57 486.2079 (M + H) 62

N-(6-(4-((1-(pyridin-2-yl)- 1H-imidazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl)propane- 2-sulfonamide 4.89 442.2018 (M + H) 63

6-(4-((1-phenyl-1H- 1,2,3-triazol-4- yl)methyl)piperazin-1-yl)pyridin-2-amine 4.40 336.1922 (M + H) 64

N-(6-(4-((1-(3- fluoropyridin-2-yl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl) cyclopropanesulfonamide 5.03457.1562 (M − H) 65

N-(6-(4-((1-(2,5- difluorophenyl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl) cyclopropanesulfonamide 5.56476.1680 (M + H) 66

N-(6-(4-((1-(2-fluoro-5- methylphenyl)-1H-1,2,3- triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl) cyclopropanesulfonamide 5.72472.1907 (M + H) 67

N-(6-(4-((1-(5- (trifluoromethyl)pyridin- 2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl) cyclopropanesulfonamide 5.82509.1684 (M + H) 68

N-(6-(4-((1-(4- (trifluoromethyl)phenyl)- 1H-1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl) cyclopropanesulfonamide 6.04508.1738 (M + H) 69

N-(6-(4-((1-(2-fluoro-4- (trifluoromethyl)phenyl)- 1H-1,2,3-triazol-4-yl)methyl)piperazin-1- yl)pyridin-2-yl) cyclopropanesulfonamide 6.05524.0   (M − H) 70

N-(6-(4-((1-phenyl-1H- imidazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl) cyclopropanesulfonamide 5.25 439.1932 (M + H) 71

N-(6-(4-((1-(2- fluorophenyl)-1H- imidazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl) cyclopropanesulfonamide 5.34 457.1824 (M + H) 72

6-(4-((1-(2- fluorophenyl)-1H-1,2,3- triazol-4- yl)methyl)piperazin-1-yl)pyridin-2-amine 4.25 376.1653 (M + Na) 73

N-(6-(4-((1-(pyridin-2-yl)- 1H-imidazol-4- yl)methyl)piperazin-1-yl)pyridin-2-yl) cyclopropanesulfonamide 4.94 440.1863 (M + H)

Biological Activity

Pharmacological Study

Human σ₁ Receptor Radioligand Assay

To investigate binding properties of σ₁ receptor ligands to human σ₁receptor, transfected HEK-293 membranes and [³H](+)-pentazocine (PerkinElmer, NET-1056), as the radioligand, were used. The assay was carriedout with 7 μg of membrane suspension, 5 nM of [³H](+)-pentazocine ineither absence or presence of either buffer or 10 μM Haloperidol fortotal and non-specific binding, respectively. Binding buffer containedTris-HCl 50 mM at pH 8. Plates were incubated at 37° C. for 120 minutes.After the incubation period, the reaction mix was then transferred toMultiScreen HTS, FC plates (Millipore), filtered and plates were washed3 times with ice-cold 10 mM Tris-HCL (pH7.4). Filters were dried andcounted at approximately 40% efficiency in a MicroBeta scintillationcounter (Perkin-Elmer) using EcoScint liquid scintillation cocktail

Human μ-Opioid Receptor Radioligand Assay

To investigate binding properties of p-opioid receptor ligands to humanp-opioid receptor, transfected CHO-K1 cell membranes and [³H]-DAMGO(Perkin Elmer, ES-542-C), as the radioligand, were used. The assay wascarried out with 20 μg of membrane suspension, 1 nM of [³H]-DAMGO ineither absence or presence of either buffer or 10 μM Naloxone for totaland non-specific binding, respectively. Binding buffer containedTris-HCl 50 mM, MgCl2 5 mM at pH 7.4. Plates were incubated at 27° C.for 60 minutes. After the incubation period, the reaction mix was thentransferred to MultiScreen HTS, FC plates (Millipore), filtered andplates were washed 3 times with ice-cold 10 mM Tris-HCL (pH 7.4).Filters were dried and counted at approximately 40% efficiency in aMicroBeta scintillation counter (Perkin-Elmer) using

EcoScint liquid scintillation cocktail.

Results:

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opiod receptor it is a very preferred embodiment in which thecompounds are selected which act as dual ligands of the σ₁ receptor andthe μ-opiod receptor and especially compounds which have a bindingexpressed as K, which is preferably <1000 nM for both receptors, morepreferably <500 nM, even more preferably <100 nM.

The following scale as been adopted for representing the binding to thethe σ₁ receptor and the μ-opiod receptor expressed as K_(i):

-   -   + Both K_(i)-μ and K_(i)-σ₁>=500 nM    -   ++ One K, <500 nM while the other K, is >=500 nM    -   +++ Both K_(i)-μ and K_(i)-σ₁<500 nM    -   ++++ Both K_(i)-μ and K_(i)-σ₁<100 nM

All compounds prepared in the present application exhibit binding to theσ₁ receptor and the μ-opiod receptor, in particular the followingbinding results are shown:

EX μ and σ₁ dual binding 1 ++++ 2 ++ 3 ++ 4 +++ 5 ++ 6 ++ 7 ++ 8 + 9++++ 10 +++ 11 +++ 12 +++ 13 +++ 14 ++++ 15 +++ 16 ++ 17 +++ 18 + 19 ++20 ++++ 21 ++ 22 ++ 23 ++ 24 + 25 +++ 26 ++++ 27 ++++ 28 +++ 29 +++ 30++++ 31 + 32 ++ 33 ++++ 34 +++ 35 ++ 36 ++++ 37 ++++ 38 +++ 39 ++++ 40+++ 41 ++ 42 +++ 43 ++ 44 +++ 45 ++ 46 ++ 47 +++ 48 ++ 49 ++ 50 ++ 51+++ 52 +++ 53 +++ 54 ++ 55 ++ 56 ++ 57 ++++ 58 ++ 59 ++ 60 +++ 61 ++ 62+++ 63 + 64 ++ 65 ++ 66 ++ 67 ++ 68 ++ 69 ++ 70 +++ 71 +++ 72 ++ 73 +++

The invention claimed is:
 1. A compound of Formula IV:

wherein m is 1 or 2; n is 0 or 1; V¹ is nitrogen or carbon; R¹ ishydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸, —SR⁶, —S(O)₂R⁶,—S(O)₂NR⁶R⁷ or —CONR⁶R⁷; R² is hydrogen, halogen, —NR⁶R⁷, —SR⁶, —OR⁶,substituted or unsubstituted alkyl, substituted or unsubstituted alkenylor substituted or unsubstituted alkynyl; wherein the alkyl, alkenyl oralkynyl in R², if substituted, is substituted with one or moresubstituents selected from F, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or—OC₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br); R³ is substituted or unsubstituted alkyl,CONR⁶R⁷, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl or substituted or unsubstituted heterocyclyl; R⁴is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted arylor substituted or unsubstituted heterocyclyl; wherein the aryl in R³and/or in R⁴, if a substituted aryl, is substituted with one or moresubstituents selected from halogen (F, Cl, I, Br), —OH, —NH₂, —SH,—C(O)OH, —OC₁₋₄alkyl being unsubstituted or substituted by one or moreof OH or halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstitutedor substituted by one or more of OH or halogen (F, Cl, I, Br); whereinthe heterocyclyl or cycloalkyl in in R³ and/or in R⁴, if a substitutedheterocyclyl or cycloalkyl, is substituted with one or more substituentsselected from halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O, —C(O)OH,—OC₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted orsubstituted by one or more of OH or halogen (F, Cl, I, Br); wherein thealkyl, alkenyl or alkynyl in R³ and/or in R⁴, if substituted, issubstituted with one or more substituents selected from F, Cl, Br, I,NH₂, SH or OH, —C(O)OH, or —OC₁₋₄alkyl being unsubstituted orsubstituted by one or more of OH or halogen (F, Cl, I, Br); R⁵ ishydrogen, hydroxy, or CH₃; R⁶, R⁷ and R⁸ are independent from each otherand selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl and substituted orunsubstituted heterocyclyl; wherein the aryl in R⁶, in R⁷, and/or in R⁸,if a substituted aryl, is substituted with one or more substituentsselected from halogen (F, Cl, I, Br), —OH, —NH₂, —SH, —C(O)OH,—OC₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted orsubstituted by one or more of OH or halogen (F, Cl, I, Br); wherein theheterocyclyl or cycloalkyl in in R⁶, in R⁷, and/or in R⁸, if asubstituted heterocyclyl or cycloalkyl, is substituted with one or moresubstituents selected from halogen (F, Cl, I, Br), —OH, —NH₂, —SH, ═O,—C(O)OH, —OC₁₋₄alkyl being unsubstituted or substituted by one or moreof OH or halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstitutedor substituted by one or more of OH or halogen (F, Cl, I, Br); whereinthe alkyl, alkenyl or alkynyl in R⁶, in R⁷, and/or in R⁸, ifsubstituted, is substituted with one or more substituents selected fromF, Cl, Br, I, NH₂, SH or OH, —C(O)OH, or —OC₁₋₄alkyl being unsubstitutedor substituted by one or more of OH or halogen (F, Cl, I, Br); and W, Yand Z are independently N or CH with only 1 or 2 of them being CH; andwherein

optionally as a stereoisomer, including enantiomers and diastereomers, aracemate or a mixture of at least two stereoisomers, includingenantiomers and/or diastereomers, in any mixing ratio, or a saltthereof; with the following proviso: with the proviso that if V¹ iscarbon, 2 of W, Y and Z are CH, n is 0 and R³ is —CH₃ or C₂H₅, then R¹may not be —NH₂.
 2. The compound according to claim 1, wherein R³ isCONR⁶R⁷, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heterocyclyl.
 3. Thecompound according to claim 2, wherein R³ is substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heterocyclyl.
 4. The compound according toclaim 1, which is a compound of Formula V:

wherein m is 1 or 2; n is 0 or 1; V¹ is nitrogen or carbon; R¹ ishydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸, —SR⁶, —S(O)₂R⁶,—S(O)₂NR⁶R⁷ or —CONR⁶R⁷; R² is hydrogen, halogen, —NR⁶R⁷, —SR⁶, —OR⁶,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, or substituted or unsubstituted alkynyl; R³ is substituted orunsubstituted alkyl, CONR⁶R⁷, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl or substituted orunsubstituted heterocyclyl; R⁴ is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedof unsubstituted aryl or substituted of unsubstituted heterocyclyl; R⁵is hydrogen, hydroxy, or CH₃; R⁶, R⁷ and R⁸ are independent from eachother and selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl and substituted orunsubstituted heterocyclyl; and wherein

optionally as a stereoisomer, including enantiomers and diastereomers, aracemate or a mixture of at least two stereoisomers, includingenantiomers and/or diastereomers, in any mixing ratio, or a saltthereof.
 5. The compound according to claim 1, wherein R¹ is hydroxyl,—NR⁶R⁷, —NR⁶S(O)₂R⁷, —SR⁶, —S(O)₂R⁶, or —S(O)₂NR⁶R⁷; R² is hydrogen,halogen, —NR⁶R⁷, —SR⁶, —OR⁶, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, or substituted or unsubstitutedalkynyl, wherein the alkyl is C₁₋₈alkyl; the alkenyl is C₂₋₁₀-alkenyl;the alkynyl is C₂₋₁₀-alkynyl; the halogen is fluorine, chlorine, iodineor bromine; R³ is substituted or unsubstituted alkyl, CONR⁶R⁷,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl or substituted or unsubstituted heterocyclyl, whereinthe aryl is phenyl, naphthyl or anthracene; the heterocyclyl is aheterocyclic ring system of one or more saturated or unsaturated ringsof which at least one ring contains one or more heteroatoms selectedfrom the group consisting of nitrogen, oxygen and sulfur; the alkyl isC₁₋₈alkyl; the alkenyl is C₂₋₁₀-alkenyl; the alkynyl is C₂₋₁₀-alkynyl;the cycloalkyl is C₃₋₈cycloalkyl; R⁴ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl or substituted orunsubstituted heterocyclyl, wherein the aryl is phenyl, naphthyl oranthracene; the heterocyclyl is a heterocyclic ring system of one ormore saturated or unsaturated rings of which at least one ring containsone or more heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur; the alkyl is C₁₋₈alkyl; the alkenyl is C₂₋₁₀-alkenyl;the alkynyl is C₂₋₁₀-alkynyl; the cycloalkyl is C₃₋₈cycloalkyl; R⁵ ishydrogen, hydroxy, or CH₃; R⁶, R⁷ and R⁸ are independent from each otherand selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl and substituted orunsubstituted heterocyclyl, wherein the aryl is phenyl, naphthyl oranthracene; the heterocyclyl is a heterocyclic ring system of one ormore saturated or unsaturated rings of which at least one ring containsone or more heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur; the alkyl is C₁₋₈alkyl; the alkenyl is C₂₋₁₀-alkenyl;the alkynyl is C₂₋₁₀-alkynyl; the cycloalkyl is C₃₋₈cycloalkyl.
 6. Thecompound according to claim 1, wherein R¹ is hydroxyl, —NR⁶R⁷,—NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, or —CONR⁶R⁷;R² is hydrogen, fluorine, CH₃ or CF₃; R³ is substituted or unsubstitutedpropyl or butyl, diethylacetamide, substituted or unsubstitutedcyclopentyl or cyclohexyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted pyridyl, imidazolyl, indenyl,2,3-dihydroindenyl, benzofuryl, or pyrimidinyl; R⁴ is hydrogen, CH₃ orCH₂OH; R⁵ is hydrogen or CH₃; and R⁶, R⁷, and R⁸ are independently fromeach other selected from the group consisting of hydrogen, substitutedor unsubstituted methyl, ethyl, propyl or butyl, substituted orunsubstituted phenyl, or substituted or unsubstituted pyrrolidinyl, orsubstituted or unsubstituted cyclopropyl.
 7. The compound according toclaim 1, wherein m is 1 or 2; n is 0 or 1; V¹ is nitrogen or carbon; R¹is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷, —NR⁶CONR⁷R⁸, —S(O)₂R⁶,—S(O)₂NR⁶R⁷, or —CONR⁶R⁷; R² is hydrogen, halogen, or C₁₋₄alkyl; R³ isselected from substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heterocyclyl; R⁴ ishydrogen or substituted or unsubstituted C₁₋₄alkyl; R⁵ is hydrogen,hydroxy, or CH₃; R⁶, R⁷, and R⁸ are independently from each otherselected from hydrogen, substituted or unsubstituted C₁₋₄alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted cycloalkyl.
 8. Thecompound according to claim 1, wherein m is 1 or 2; n is 0 or 1; V¹ isnitrogen or carbon; R¹ is hydroxyl, —NR⁶R⁷, —NR⁶S(O)₂R⁷, —NR⁶COR⁷,—NR⁶CONR⁷R⁸, —S(O)₂R⁶, —S(O)₂NR⁶R⁷, or —CONR⁶R⁷; R² is hydrogen; R³ issubstituted or unsubstituted cyclopentyl, cyclohexyl, substituted orunsubstituted phenyl, or substituted or unsubstituted pyridyl,imidazolyl, indenyl, 2,3-dihydroindenyl, benzofuryl, or pyrimidinyl; R⁴is hydrogen or substituted or unsubstituted C₁₋₄alkyl; R⁵ is hydrogen,hydroxy, or CH₃; R⁶, R⁷ and R⁸ are independent from each other andselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₄alkyl, substituted or unsubstituted C₃₋₆cycloalkyl,and substituted or unsubstituted phenyl; and W, Y and Z areindependently from one another N or CH with only 1 or 2 of them beingCH; and wherein

optionally as a stereoisomer, including enantiomers and diastereomers, aracemate or a mixture of at least two stereoisomers, includingenantiomers and/or diastereomers, in any mixing ratio, or a saltthereof.
 9. The compound according to claim 1 which is selected from:N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyphexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)methanesulfonamide,N-(3-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyphexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)propane-2-sulfonamide,N-(6-(5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyphexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,N-(6-(5-((1-benzyl-1H-1,2,3-triazol-4-yl)methyphexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,N-(6-(5-((1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,andN-(6-(5-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyphexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)propane-2-sulfonamide,optionally as a stereoisomer, including enantiomers and diastereomers, aracemate or a mixture of at least two stereoisomers, includingenantiomers and/or diastereomers, in any mixing ratio, or a saltthereof.
 10. A process for the production of a compound of formula Vaccording to claim 4

wherein R¹, R², R³, R⁴, R⁵, n and m as well as

 are as defined in claim 4, wherein a compound of formula VIII or itssuitable salt,

wherein R¹R² and R⁵ are as defined in claim 4, is reacted with acompound of formula X under the conditions of Step 2

wherein m is as defined in claim 4, leading to a compound of formula IX,

wherein R¹, R², R⁵ and m are as defined in claim 4, followed by reactingthe compound of formula IX with a compound of formula XI under theconditions of Step 3

wherein R³, R⁴ and n are as defined in claim 4, under the conditions ofStep 3, leading to a compound of formula (V), wherein X is a leavinggroup, wherein the reaction of Step 2 of the compounds of formula (VIII)with the compounds of formula (X) is carried out in the presence of abase in an aprotic solvent, wherein the reaction of Step 3 of thecompounds of formula (IX) with the compounds of formula (XI) is carriedout in the presence of a copper salt and sodium ascorbate in a mixtureof protic organic solvent and water.
 11. A pharmaceutical compositionwhich comprises the compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,adjuvant or vehicle.
 12. A method for treating pain in a subject in needthereof, comprising administration of an effective amount of thecompound according to claim
 1. 13. The method of claim 12, wherein thepain is medium to severe pain, visceral pain, chronic pain, cancer pain,migraine, inflammatory pain, acute pain or neuropathic pain, allodyniaor hyperalgesia.